* 120150

COLLAGEN, TYPE I, ALPHA-1; COL1A1


Alternative titles; symbols

COLLAGEN OF SKIN, TENDON, AND BONE, ALPHA-1 CHAIN


Other entities represented in this entry:

COL1A1/PDGFB FUSION GENE, INCLUDED

HGNC Approved Gene Symbol: COL1A1

Cytogenetic location: 17q21.33     Genomic coordinates (GRCh38): 17:50,184,101-50,201,631 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
17q21.33 {Bone mineral density variation QTL, osteoporosis} 166710 AD 3
Caffey disease 114000 AD 3
Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 619115 AD 3
Ehlers-Danlos syndrome, arthrochalasia type, 1 130060 AD 3
Osteogenesis imperfecta, type I 166200 AD 3
Osteogenesis imperfecta, type II 166210 AD 3
Osteogenesis imperfecta, type III 259420 AD 3
Osteogenesis imperfecta, type IV 166220 AD 3

TEXT

Description

Collagen has a triple-stranded rope-like coiled structure. The major collagen of skin, tendon, and bone is the same protein containing 2 alpha-1 polypeptide chains and 1 alpha-2 chain. Although these are long (the procollagen chain has a molecular mass of about 120 kD, before the 'registration peptide' is cleaved off; see 225410), each messenger RNA is monocistronic (Lazarides and Lukens, 1971). Differences in the collagens from these 3 tissues are a function of the degree of hydroxylation of proline and lysine residues, aldehyde formation for cross-linking, and glycosylation. The alpha-1 chain of the collagen of cartilage and that of the collagen of basement membrane are determined by different structural genes. The collagen of cartilage contains only 1 type of polypeptide chain, alpha-1, and this is determined by a distinct locus. The fetus contains collagen of distinctive structure. The genes for types I, II, and III collagens, the interstitial collagens, exhibit an unusual and characteristic structure of a large number of relatively small exons (54 and 108 bp) at evolutionarily conserved positions along the length of the triple-helical gly-X-Y portion (Boedtker et al., 1983). The family of collagen proteins consists of a minimum of 9 types of collagen molecules whose constituent chains are encoded by a minimum of 17 genes (Ninomiya and Olsen, 1984).


Cloning and Expression

Tromp et al. (1988) characterized a full-length cDNA clone for the COL1A1 gene.


Mapping

Sundar Raj et al. (1977) used the methods of cell hybridization and microcell hybridization to assign a collagen I gene to chromosome 17. Solomon and Sykes (1979) concluded, incorrectly as it turned out, that both the alpha-1 and the alpha-2 genes of collagen I are on chromosome 7. Solomon and Sykes (1979) also presented evidence that the alpha-1 chains of collagen III are also coded by chromosome 7. Church et al. (1981) assigned a structural gene for corneal type I procollagen to chromosome 7 by somatic cell hybridization involving corneal stromal fibroblasts. Because they had previously assigned a gene for skin type I procollagen to chromosome 17, they wondered whether skin and corneal type I collagen may be under separate control.

Huerre et al. (1982) used a cDNA probe in both mouse-man and Chinese hamster-man somatic cell hybrids to demonstrate cosegregation with human chromosome 17. In situ hybridization using the same probe indicated that the gene is in the middle third of the long arm, probably in band 17q21 or 17q22.

By chromosome-mediated gene transfer (CMGT), Klobutcher and Ruddle (1979) transferred the genes for thymidine kinase, galactokinase (604313), and type I procollagen (gene for alpha-1 polypeptide). The data indicated the following gene order: centromere--GALK--(TK1-COL1A1). Later studies (Ruddle, 1982) put the growth hormone gene cluster (see 139250) between GALK and (TK1-COL1A1).

A HindIII restriction site polymorphism in the alpha-1(I) gene was described by Driesel et al. (1982), who probably unjustifiably stated that the gene is on chromosome 7. By in situ hybridization, Retief et al. (1985) concluded that the alpha-1(I) and alpha-2(I) genes are located in bands 17q21.31-q22.05 and 7q21.3-q22.1, respectively.

Sippola-Thiele et al. (1986) commented on the limited number of informative RFLPs in the collagen genes, especially COL1A1. They proposed a method for assessing RFLPs that were otherwise undetectable in total human genomic DNA. Using the centromere-based locus D17Z1, Tsipouras et al. (1988) found a recombination fraction of 0.20 with COL1A1. Furthermore, they demonstrated that COL1A1 and GH1 (139250) show a recombination fraction of 0.10. They proposed that the most likely order is D17Z1--COL1A1--GH1.

Shupp Byrne and Church (1983) had concluded that both subunits of type I collagen, alpha-1 and alpha-2, are coded by chromosome 16 in the mouse. SOD1 (147450), which in man is on chromosome 21, is also carried by mouse 16. It may have been type VI collagen (120220, 120240) that they dealt with; both COL6A1 and COL6A2 are coded by human chromosome 21. (In fact, the Col6a1 and Col6a2 genes are carried by mouse chromosome 10 (Justice et al., 1990).) Munke et al. (1986) showed that the alpha-1 gene of type I collagen is located on mouse chromosome 11; the Moloney murine leukemia virus is stably integrated into this site when microinjected into the pronuclei of fertilized eggs. This insertion results in a lethal mutation through blockage of the developmentally regulated expression of the gene (Schnieke et al., 1983).


Molecular Genetics

Amino Acid Numbering System for COL1A1

Conventional numbering for the alpha-1(I) amino acid residues begins with the first glycine at the N-terminal end of the triple-helical domain. This numbering system is used in the list of allelic variants below.

Osteogenesis Imperfecta

Pope et al. (1985) described a substitution of cysteine in the C-terminal end of the alpha-1 collagen chain in a 9-year-old boy with mild osteogenesis imperfecta (OI) of Sillence type I (OI1; 166200). They assumed that this was a substitution for either arginine or serine (which could be accomplished by a single base change) because substitution of cysteine for glycine produced a much more drastic clinical picture. In a neonatal lethal case of OI congenita, or type II (OI2; 166210), Barsh and Byers (1981) demonstrated a defect in pro-alpha-1 chains

Byers et al. (1988) found an insertion in one COL1A1 allele in an infant with OI2. One alpha-1 chain was normal in length, whereas the other contained an insertion of approximately 50-70 amino acid residues within the triple-helical domain defined by amino acids 123-220. The structure of the insertion was consistent with duplication of an approximately 600-bp segment in 1 allele.

Brookes et al. (1989) used an S1 nuclease directed cleavage of heteroduplex DNA molecules formed between genomic material and cloned sequences to search for mutations in the COL1A1 gene in 5 cases in which previous linkage studies had shown the mutation to be located in the COL1A1 gene and in 4 cases in which a COL1A1 null allele had been identified by protein and RNA studies. No abnormality was found in the complete 18 kb COL1A1 gene or in 2 kb of 5-prime flanking sequence. The method used was known to permit the detection of short length variations of the order of 4 bp in heterozygous subjects but not single basepair alterations. Thus, Brookes et al. (1989) suggested that single basepair alterations may be the predominant category of mutation in type I OI.

COL1A1 and NGFR (162010) are in the same restriction fragment. In a 3-generation family with OI type I, Willing et al. (1990) found that all affected members had one normal COL1A1 allele and another from which the intragenic EcoRI restriction site near the 3-prime end of the gene was missing. They found, furthermore, a 5-bp deletion at the EcoRI site which changed the translational reading frame and predicted the synthesis of a pro-alpha-1(I) chain that extended 84 amino acids beyond the normal termination. Although the mutant chain was synthesized in an in vitro translation system, they were unable to detect its presence in intact cells, suggesting that it is unstable and rapidly destroyed in one of the cell's degradative pathways.

Cohn et al. (1990) demonstrated a clear instance of paternal germline mosaicism as the cause of 2 offspring with OI type I by different women. Both affected infants had a G-to-A change that resulted in substitution of aspartic acid for glycine at position 883 of the alpha-1 chain of type I collagen. Although not detected in the father's skin fibroblasts, the mutation was detected in somatic DNA from the father's hair root bulbs and lymphocytes. It was also found in the father's sperm where about 1 in 8 sperm carried the mutation, suggesting that at least 4 progenitor cells populate the germline in human males. The father was clinically normal. In an infant with perinatal lethal OI (OI type II), Wallis et al. (1990) demonstrated both normal and abnormal type I procollagen molecules. The abnormal molecules had substitution of arginine for glycine at position 550 of the triple-helical domain as a result of a G-to-A transition in the first base of the glycine codon. The father was shown to be mosaic for this mutation, which accounted for about 50% of the COL1A1 alleles in his fibroblasts, 27% of those in blood cells, and 37% of those in sperm. The father was short of stature; he had bluish sclerae, grayish discoloration of the teeth (which were small), short neck, barrel-shaped chest, right inguinal hernia, and hyperextensible fingers and toes. A triangular-shaped head had been noted at birth and he was thought to have hydrocephalus. No broken bones had been noted at that time. He had had only 1 fracture, that of the clavicle at age 8 years.

Cole et al. (1990) reported the clinical features of 3 neonates with lethal perinatal OI resulting from a substitution of glycine by arginine in the COL1A1 gene product. The mutations were gly391-to-arg, gly667-to-arg, and gly976-to-arg. All 3 were small, term babies who died soon after birth. The ribs were broad and continuously beaded in the first, discontinuously beaded in the second, and slender with few fractures in the third. The overall radiographic classifications were type IIA, IIA/IIB, and IIB, respectively (based on an old classification by Sillence et al., 1984; see HISTORY in 166210). The findings suggested that there was a gradient of bone modeling capacity from the slender and overmodeled bones associated with the mutation nearest the C-terminal end of the molecule to absence of modeling with that nearest the N-terminal end.

Dermal fibroblasts from most persons with OI type I produce about half the normal amount of type I procollagen as a result of decreased synthesis of one of its constituent chains, namely, the alpha-1 chain. Willing et al. (1992) used a polymorphic MnlI restriction endonuclease site in the 3-prime untranslated region of COL1A1 to distinguish the transcripts of the 2 alleles in 23 heterozygotes from 21 unrelated families with OI type I. In each case there was marked diminution in steady-state mRNA levels from one COL1A1 allele. They demonstrated that loss of an allele through deletion or rearrangement was not the cause of the diminished COL1A1 mRNA levels. Primer extension with nucleotide-specific chain termination allowed identification of the mutant allele in cell strains that were heterozygous for an expressed polymorphism. Willing et al. (1992) suggested that the method is applicable to sporadic cases, to small families, and to large families in which key persons are uninformative at the polymorphic sites used in linkage analysis.

Willing et al. (1993) pointed out that the abnormally low ratio of COL1A1 mRNA to COL1A2 (120160) mRNA in fibroblasts cultured from OI type I patients is an indication of a defect in the COL1A1 gene in the great majority of patients with this form of OI.

Byers (1993) counted a total of approximately 70 point mutations identified in the helical portion of the alpha-1 peptide, approximately 10 exon skipping mutations, and about 6 point mutations in the C-propeptide.

Steady state amounts of COL1A1 mRNA are reduced in both the nucleus and cytoplasm of dermal fibroblasts from most subjects with type I osteogenesis imperfecta (166200). Willing et al. (1995) investigated whether mutations involving key regulatory sequences in the COL1A1 promoter, such as the TATAAA and CCAAAT boxes, are responsible for the reduced levels of mRNA. They used PCR-amplified genomic DNA in conjunction with denaturing gradient gel electrophoresis and SSCP to screen the 5-prime untranslated domain, exon 1, and a small portion of intron 1 of the COL1A1 gene. In addition, direct sequence analysis was performed on an amplified genomic DNA fragment that included the TATAAA and CCAAAT boxes. In a survey of 40 unrelated probands with OI type I in whom no causative mutation was known, Willing et al. (1995) identified no mutations in the promoter region and there was 'little evidence of sequence diversity among any of the 40 subjects.'

Whereas most cases of severe osteogenesis imperfecta result from mutations in the coding region of the COL1A1 or COL1A2 genes yielding an abnormal collagen alpha-chain, many patients with mild OI show evidence of a null allele due to a premature stop mutation in the mutant RNA transcript. As indicated in 120150.0046, mild OI in one case resulted from a null allele arising from a splice donor mutation where the transcript containing the included intron was sequestered in the nucleus. Nuclear sequestration precluded its translation and thus rendered the allele null. Using RT-PCR and SSCP of COL1A1 mRNA from patients with mild OI, Redford-Badwal et al. (1996) identified 3 patients with distinct null-producing mutations identified from the mutant transcript within the nuclear compartment. In a fourth patient with a gly-to-arg expressed point mutation, they found the mutant transcript in both the nucleus and the cytoplasm.

Willing et al. (1996) analyzed the effects of nonsense and frameshift mutations on steady-state levels of COL1A1 mRNA. Total cellular and nuclear RNA was analyzed. They found that mutations which predict premature termination reduce steady-state amounts of COL1A1 mRNA from the mutant allele in both nuclear and cellular mRNA. The investigators concluded that premature termination mutations have a predictable and uniform effect on COL1A1 gene expression which ultimately leads to decreased production of type I collagen and to the mild phenotype associated with OI type I. Willing et al. (1996) reported that mutations which lead to premature translation termination appear to be the most common molecular cause of OI type I. They identified 21 mutations, 15 of which lead to premature termination as a result of translational frameshifts or single-nucleotide substitutions. Five mutations were splicing defects leading to cryptic splicing or intron retention within the mature mRNA. Both of these alternative splicing pathways indirectly lead to frameshifts and premature termination in downstream exons.

In 4 apparently unrelated patients with OI, Korkko et al. (1997) found 2 new recurrent nucleotide mutations in the COL1A1 gene, using a protocol whereby 43 exons and exon-flanking sequences were amplified by PCR and scanned for mutations by denaturing gradient gel electrophoresis. From an analysis of previous publications, they concluded that up to one-fifth of mutations causing OI are recurrent in the sense that they are identical in apparently unrelated probands. About 80% of these identical mutations were found to be in CpG dinucleotide sequences. Korkko et al. (1997) tabulated reported cases of recurrent mutations causing OI. The most frequent recurrent mutation was gly352ser (120150.0042), reported in 4 unrelated patients. They also reported a nonsense mutation in the codon for arginine-963 (120150.0055).

Since collagen I consists of 2 alpha-1 chains and 1 alpha-2 chain, a mutation in the COL1A1 gene might affect the function of the collagen molecule more than would a similar substitution in the COL1A2 gene, thereby causing more severe OI, for example. Lund et al. (1997) tested this hypothesis by comparing patients with identical substitutions in different alpha chains. They presented a G586V substitution in the alpha-1 gene (120150.0056) and compared it with a G586V substitution in the alpha-2 gene (120160.0023). Their patient had lethal OI type II. Patients with the same substitution in the alpha-2 chain had either OI type IV (OI4; 166220) or type III (OI3; 259420). Lund et al. (1997) pointed out that identical biochemical alterations in the same chain are known to have different phenotypic effects, both within families and between unrelated patients. They took this into account in their cautious proposal that substitutions in the alpha-1 chain may have more serious consequences than similar substitutions in the alpha-2 chain.

Kuivaniemi et al. (1997) summarized the data on 278 different mutations found in genes for types I, II, III, IX, X, and XI collagens from 317 apparently unrelated patients. Most mutations (217; 78% of the total) were single-base and either changed the codon of a critical amino acid (63%) or led to abnormal RNA splicing (13%). Most (155; 56%) of the amino acid substitutions were those of a bulkier amino acid replacing the obligatory glycine of the repeating Gly-X-Y sequence of the collagen triple helix. Altogether, 26 different mutations (9.4%) occurred in more than 1 unrelated individual. The 65 patients in whom the 26 mutations were characterized constituted almost one-fifth (20.5%) of the 317 patients analyzed. The mutations in these 6 collagens caused a wide spectrum of diseases of bone, cartilage, and blood vessels, including osteogenesis imperfecta, a variety of chondrodysplasias, types IV (130050) and VII (130060) Ehlers-Danlos syndrome, and, rarely, some forms of osteoporosis, osteoarthritis, and familiar aneurysms.

Dalgleish (1997) described a mutation database for the COL1A1 and COL1A2 genes.

Mutations in the COL1A2 gene appear to be very rare causes of type I osteogenesis imperfecta. Korkko et al. (1998) developed a method for analysis of the COL1A1 and COL1A2 genes in 15 patients with type I OI and found only COL1A1 mutations. They described their protocols for PCR amplification of the exon and exon boundaries of all 103 exons in the COL1A1 and COL1A2 genes. As previously pointed out, most mutations found in patients with OI type I introduce either premature termination codons or aberrant RNA splicing and thereby reduce the expression of the COL1A1 gene. The mutations tend to occur in common sequence context. All 9 mutations, found by Korkko et al. (1998) to convert the arginine codon CGA to the premature-termination codon TGA, occurred in the sequence context of G/CCC CGA GG/T of the COL1A1 gene. None was found in 7 CGA codons for arginine in other sequence contexts of the COL1A1 gene. The COL1A1 gene has 6 such sequences, whereas the COL1A2 gene has none.

Triple helix formation is a prerequisite for the passage of type I procollagen from the endoplasmic reticulum and secretion from the cell to form extracellular fibrils that will support mineral deposition in bone. In an analysis of cDNA from 11 unrelated individuals with osteogenesis imperfecta, Pace et al. (2001) found 11 novel, short in-frame deletions or duplications of 3, 9, or 18 nucleotides in the helical coding regions of the COL1A1 or COL1A2 collagen genes. Triple helix formation was impaired, type I collagen alpha chains were posttranslationally overmodified, and extracellular secretion was markedly reduced. With one exception, the obligate Gly-Xaa-Yaa repeat pattern of amino acids in the helical domains was not altered, but the Xaa and Yaa position residues were out of register relative to the amino acid sequences of adjacent chains in the triple helix. Thus, the identity of these amino acids, in addition to third position glycines, is important for normal helix formation. These findings expanded the repertoire of uncommon in-frame deletions and duplications in OI, and provided insight into normal collagen biosynthesis and collagen triple helix formation.

Cabral et al. (2001) reported a 13-year-old girl with severe type III OI in whom they identified heterozygosity for a gly76-to-glu substitution in the COL1A1 gene (120150.0065). The authors stated that this was the first delineation of a glutamic acid substitution in the alpha-1(I) chain causing nonlethal osteogenesis imperfecta.

Chamberlain et al. (2004) used adeno-associated virus vectors to disrupt dominant-negative mutant COL1A1 collagen genes in mesenchymal stem cells, also known as marrow stromal cells, from individuals with severe OI, demonstrating successful gene targeting in adult human stem cells.

Ehlers-Danlos Syndrome

In a girl with EDS VIIA (EDSARTH1; 130060) reported by Cole et al. (1986), Weil et al. (1989) identified a de novo heterozygous mutation in the COL1A1 gene that resulted in the skipping of exon 6 (120150.0026). The deleted peptides included those encoding the N-proteinase cleavage site necessary for proper collagen processing. D'Alessio et al. (1991) identified the same COL1A1 mutation in another child with EDS VIIA.

In a girl with EDSARTH1, Byers et al. (1997) identified a heterozygous splice site mutation in the COL1A1 gene, resulting in the skipping of exon 6 (120150.0057).

In a girl with severe EDSARTH1, Giunta et al. (2008) identified a heterozygous splice site mutation in the COL1A1 gene, resulting in the skipping of exon 6 (120150.0066).

In 2 unrelated patients with classic EDS (EDSCL1; 130000), Nuytinck et al. (2000) identified an arg134-to-cys mutation (120150.0059) in the COL1A1 gene.

Combined Osteogenesis Imperfecta and Ehlers-Danlos Syndrome 1

In 7 children with combined osteogenesis imperfecta and Ehlers-Danlos syndrome-1 (OIEDS1; 619115), Cabral et al. (2005) identified heterozygous mutations in the COL1A1 gene (see, e.g., 120150.0064). All of the mutations occurred in the first 90 residues of the helical region of alpha-1(I) collagen. These mutations prevented or delayed removal of the procollagen N-propeptide by purified N-proteinase (ADAMTS2; 604539) in vitro and in pericellular assays. The mutant pN-collagen which resulted was efficiently incorporated into matrix by cultured fibroblasts and osteoblasts and was prominently present in newly incorporated and immaturely cross-linked collagen. Dermal collagen fibrils had significantly reduced cross-sectional diameters, corroborating incorporation of pN-collagen into fibrils in vivo. The mutations disrupted a distinct folding region of high thermal stability in the first 90 residues at the amino end of type I collagen and altered the secondary structure of the adjacent N-proteinase cleavage site. Thus, these mutations are directly responsible for the bone fragility of OI and indirectly responsible for EDS symptoms, by interference with N-propeptide removal.

Cabral et al. (2005) hypothesized that the nature of EDS-like symptoms in OIEDS patients is similar to type VII EDS derived primarily by deletions of the N-propeptide cleavage site in alpha-1(I) and alpha-2(I) (120160) chains, in EDS VIIA (EDSARTH1; 130060) and VIIB (EDSARTH2; 617821), respectively, or by N-proteinase deficiency in EDS VIIC (EDSDRMS; 225410). It remained unclear why alpha-1(I)-OI/EDS patients had a somewhat different EDS phenotype (e.g., pronounced early scoliosis and no bilateral hip dysplasia) and why their collagen fibrils had more rounded cross-section under electron microscopy investigation. Makareeva et al. (2006) demonstrated that 85 N-terminal amino acids of the alpha1(I) chain participate in a highly stable folding domain, acting as the stabilizing anchor for the amino end of the type I collagen triple helix. This anchor region is bordered by a microunfolding region, 15 amino acids in each chain, which includes no proline or hydroxyproline residues and contains a chymotrypsin cleavage site. Glycine substitutions and amino acid deletions within the N-anchor domain induced its reversible unfolding above 34 degrees C. The overall triple helix denaturation temperature was reduced by 5 to 6 degrees C, similar to complete N-anchor removal. N-propeptide partially restored the stability of mutant procollagen but not sufficiently to prevent N-anchor unfolding and a conformational change at the N-propeptide cleavage site. The ensuing failure of N-proteinase to cleave at the misfolded site led to incorporation of pN-collagen into fibrils. As in EDS VIIA/B, fibrils containing pN-collagen are thinner and weaker causing EDS-like laxity of large and small joints and paraspinal ligaments. Makareeva et al. (2006) concluded that distinct structural consequences of N-anchor destabilization result in a distinct alpha1(I)-OI/EDS phenotype.

In 4 patients in a small pedigree with OIEDS, Cabral et al. (2007) identified heterozygosity for a c.3196C-T transition in the COL1A1 gene (120150.0071), resulting in an arg888-to-cys substitution in the Y position of one of the Gly-X-Y triplets that compose the collagen helix. The substitution in the Y position was shown to result in less delay in helix formation than would have been expected for a glycine substitution. Disulfide-bonded dimers of alpha(I) chains formed inefficiently in helices with 2 mutant chains; however, secretion from cells was normal. Formation of disulfide dimers at position 888 resulted in helix kinking, with resulting decreased helix stability and propagation of altered secondary structure along the remaining helix.

Malfait et al. (2013) sequenced the COL1A1 and COL1A2 genes in 7 patients with OIEDS1 or OIEDS2 (see 619120) and identified heterozygous mutations in the most N-terminal part of the type I collagen helix (2 in COL1A1 and 5 in COL1A2) in all patients. Both mutations in COL1A1 were missense (G188D; 120150.0072 and G203C) and the mutations in COL1A2 were 3 exon skipping and 2 missense. The mutations affected the rate of type I collagen N-propeptide cleavage and disturbed normal collagen fibrillogenesis.

By Sanger sequencing in a patient with OIEDS, Symoens et al. (2017) identified an in-frame 9-bp deletion in exon 44 of the COL1A1 gene (c.3150_3158del; 120150.0073), resulting in deletion of 3 amino acids in the collagen triple helix. The mutation was found to be present in mosaic state, which the authors concluded was responsible for the mild symptoms in the patient.

Caffey Disease

In affected individuals and obligate carriers from 3 unrelated families with Caffey disease (CAFYD; 114000), Gensure et al. (2005) identified heterozygosity for an arg836-to-cys mutation (R836C; 120150.0063) in the COL1A1 gene. Kamoun-Goldrat et al. (2008) identified heterozygosity for the R836C mutation in the COL1A1 gene in the pulmonary tissue of a fetus with a severe form of prenatal cortical hyperostosis (see 114000) from a terminated pregnancy at 30 weeks' gestation. The authors speculated that mutation in another gene might also be involved.

Susceptibility to Osteoporosis

Osteoporosis (166710) is a common disorder with a strong genetic component. One way in which the genetic component could be expressed is through polymorphism of COL1A1. Grant et al. (1996) described a novel G-to-T transversion at the first base of a binding site for the transcription factor Sp1 (189906) in intron 1 of COL1A1 (rs1800012; 120150.0051). They found that the polymorphism was associated with low bone density and increased appearance of osteoporotic vertebral fractures in 299 British women. In a study of 1,778 postmenopausal Dutch women, Uitterlinden et al. (1998) confirmed the association of the Sp1-binding site polymorphism and bone mineral density.

Lohmueller et al. (2003) performed a metaanalysis of 301 published genetic association studies covering 25 different reported associations. For 8 of the 25 associations, strong evidence of replication of the initial report was available. One of these 8 was the association between COL1A1 and osteoporotic fracture as first reported by Grant et al. (1996). Of a G/T SNP in intron 1, osteoporotic fractures showed association with the T allele.

In 1,873 Caucasian subjects from 405 nuclear families, Long et al. (2004) examined the relationship between 3 SNPs in the COL1A1 gene and bone size at the spine, hip, and wrist. They found suggestive evidence for an association with wrist size at SNP2 (p = 0.011): after adjusting for age, sex, height, and weight, subjects with the T allele of SNP2 had, on average, a 3.05% smaller wrist size than noncarriers. Long et al. (2004) concluded that the COL1A1 gene may have some effect on bone size variation at the wrist, but not at the spine or hip, in these families.

Jin et al. (2009) showed that the previously reported 5-prime untranslated region (UTR) SNPs in the COL1A1 gene (-1997G-T, rs1107946, 120150.0067; -1663indelT, rs2412298, 120150.0068; +1245G-T, rs1800012) affected COL1A1 transcription. Transcription was 2-fold higher with the osteoporosis-associated G-del-T haplotype compared with the common G-ins-G haplotype. The region surrounding rs2412298 recognized a complex of proteins essential for osteoblast differentiation and function including NMP4 (ZNF384; 609951) and Osterix (SP7; 606633), and the osteoporosis-associated -1663delT allele had increased binding affinity for this complex. Further studies showed that haplotype G-del-T had higher binding affinity for RNA polymerase II, consistent with increased transcription of the G-del-T allele, and there was a significant inverse association between carriage of G-del-T and bone mineral density (BMD) in a cohort of 3,270 Caucasian women. Jin et al. (2009) concluded that common polymorphic variants in the 5-prime UTR of COL1A1 regulate transcription by affecting DNA-protein interactions, and that increased levels of transcription correlated with reduced BMD values in vivo by altering the normal 2:1 ratio between alpha-1(I) and alpha-2(I) chains.


Genotype/Phenotype Correlations

Di Lullo et al. (2002) stated that binding sites on type I collagen had been elucidated for approximately half of the almost 50 molecules that had been found to interact with it. In addition, more than 300 mutations in type I collagen associated with human connective tissue disorders had been described. However, the spatial relationships between the ligand-binding sites and mutation positions had not been examined. Di Lullo et al. (2002) therefore created a map of type I collagen that included all of its ligand-binding sites and mutations. The map revealed several hotspots for ligand interactions on type I collagen and showed that most of the binding sites locate to its C-terminal half. Moreover, some potentially relevant relationships between binding sites were observed on the collagen fibril, including the following: fibronectin- and certain integrin-binding regions are near neighbors, which may mechanistically relate to fibronectin-dependent cell-collagen attachment; proteoglycan binding may influence collagen fibrillogenesis, cell-collagen attachment, and collagen glycation seen in diabetes and aging; and mutations associated with osteogenesis imperfecta and other disorders show apparently nonrandom distribution patterns within both the monomer and fibril, implying that mutation positions correlate with disease phenotype.

A missense mutation leading to the replacement of 1 Gly in the (Gly-Xaa-Yaa)n repeat of the collagen triple helix can cause a range of heritable connective tissue disorders that depend on the gene in which the mutation occurs. Persikov et al. (2004) found that the spectrum of amino acids replacing Gly was not significantly different from that expected for the COL7A1 (120120)-encoded collagen chains, suggesting that any Gly replacement will cause dystrophic epidermolysis bullosa (604129). On the other hand, the distribution of residues replacing Gly was significantly different from that expected for all other collagen chains studied, with a particularly strong bias seen for the collagen chains encoded by COL1A1 and COL3A1 (120180). The bias did not correlate with the degree of chemical dissimilarity between gly and the replacement residues, but in some cases a relationship was observed with the predicted extent of destabilization of the triple helix. Of the COL1A1-encoded chains, the most destabilizing residues (valine, glutamic acid, and aspartic acid) and the least destabilizing residue (alanine) were underrepresented. This bias supported the hypothesis that the level of triple-helix destabilization determines clinical outcome.

In an extensive review of published and unpublished sources, Marini et al. (2007) identified and assembled 832 independent mutations in the type I collagen genes (493 in COL1A1 and 339 in COL1A2). There were 682 substitutions of glycine residues within the triple-helical domains of the proteins (391 in COL1A1 and 291 in COL1A2) and 150 splice site mutations (102 in COL1A1 and 48 in COL1A2). One-third of the mutations that result in glycine substitutions in COL1A1 were lethal, whereas substitutions in the first 200 residues were nonlethal and had variable outcomes unrelated to folding or helix stability domains. Two exclusively lethal regions, helix positions 691-823 and 910-964, aligned with major ligand binding regions. Mutations in COL1A2 were predominantly nonlethal (80%), but lethal regions aligned with proteoglycan bindings sites. Splice site mutations accounted for 20% of helical mutations, were rarely lethal, and often led to a mild phenotype.

Rauch et al. (2010) compared the results of genotype analysis and clinical examination in 161 patients who were diagnosed as having OI type I, III, or IV according to the Sillence classification (median age: 13 years) and had glycine mutations in the triple-helical domain of alpha-1(I) (n = 67) or alpha-2(I) (n = 94). There were 111 distinct mutations, of which 38 affected the alpha-1(I) chain and 73 the alpha-2(I) chain. Serine substitutions were the most frequently encountered type of mutation in both chains. Overall, the majority of patients had a phenotypic diagnosis of OI type III or IV, had dentinogenesis imperfecta and blue sclera, and were born with skeletal deformities or fractures. Compared with patients with serine substitutions in alpha-2(I) (n = 40), patients with serine substitutions in alpha-1(I) (n = 42) on average were shorter (median height z-score -6.0 vs -3.4; P = 0.005), indicating that alpha-1(I) mutations cause a more severe phenotype. Height correlated with the location of the mutation in the alpha-2(I) chain but not in the alpha-1(I) chain. Patients with mutations affecting the first 120 amino acids at the N-terminal end of the collagen type I triple helix had blue sclera but did not have dentinogenesis imperfecta. Among patients from different families sharing the same mutation, about 90% and 75% were concordant for dentinogenesis imperfecta and blue sclera, respectively.

Takagi et al. (2011) reported 4 Japanese patients, including 2 unrelated patients with what the authors called 'classic OI IIC' and 2 sibs with features of 'OI IIC' but less distortion of the tubular bones (OI dense bone variant). No consanguinity was reported in their parents. In both sibs and 1 sporadic patient, they identified heterozygous mutations in the C-propeptide region of COL1A1 (120150.0069 and 120150.0070, respectively), whereas no mutation in this region was identified in the other sporadic patient. Familial gene analysis revealed somatic mosaicism of the mutation in the clinically unaffected father of the sibs, whereas their mother and healthy older sister did not have the mutation. Histologic examination in the 2 sporadic cases showed a network of broad, interconnected cartilaginous trabeculae with thin osseous seams in the metaphyseal spongiosa. Thick, cartilaginous trabeculae (cartilaginous cores) were also found in the diaphyseal spongiosa. Chondrocyte columnization appeared somewhat irregular. These changes differed from the narrow and short metaphyseal trabeculae found in other lethal or severe cases of OI. Takagi et al. (2011) concluded that heterozygous C-propeptide mutations in the COL1A1 gene may result in OI IIC with or without twisting of the long bones and that OI IIC appears to be inherited as an autosomal dominant trait.


Cytogenetics

COL1A1/PDGFB Fusion Gene

Dermatofibrosarcoma protuberans (DFSP; 607907), an infiltrative skin tumor of intermediate malignancy, presents specific cytogenetic features such as reciprocal translocations t(17;22)(q22;q13) and supernumerary ring chromosomes derived from t(17;22). Simon et al. (1997) characterized the breakpoints from translocations and rings in dermatofibrosarcoma protuberans and its juvenile form, giant cell fibroblastoma, on the genomic and RNA levels. They found that these rearrangements fuse the PDGFB gene (190040) and the COL1A1 gene. Simon et al. (1997) commented that PDGFB has transforming activity and is a potent mitogen for a number of cell types, but its role in oncogenic processes was not fully understood. They noted that neither COL1A1 nor PDGFB had hitherto been implicated in tumor translocations. The gene fusions deleted exon 1 of PDGFB and released this growth factor from its normal regulation; see 190040.0002.

Nakanishi et al. (2007) used RT-PCR to examine the COL1A1/PDGFB transcript using frozen biopsy specimens from 3 unrelated patients with DFSP and identified fusion of COL1A1 exon 25, exon 31, and exon 46, respectively, to exon 2 of the PDGFB gene. Clinical features and histopathology did not demonstrate any specific characteristics associated with the different transcripts.


Biochemical Features

Gauba and Hartgerink (2008) reported the design of a novel model system based upon collagen-like heterotrimers that can mimic the glycine mutations present in either the alpha-1 or alpha-2 chains of type I collagen. The design utilized an electrostatic recognition motif in 3 chains that can force the interaction of any 3 peptides, including AAA (all same), AAB (2 same and 1 different), or ABC (all different) triple helices. Therefore, the component peptides could be designed in such a way that glycine mutations were present in zero, 1, 2, or all 3 chains of the triple helix. They reported collagen mutants containing 1 or 2 glycine substitutions with structures relevant to native forms of OI. Gauba and Hartgerink (2008) demonstrated the difference in thermal stability and refolding half-life times between triple helices that vary only in the frequency of glycine mutations at a particular position.

By differential scanning calorimetry and circular dichroism, Makareeva et al. (2008) measured and mapped changes in the collagen melting temperature (delta-T(m)) for 41 different glycine substitutions from 47 OI patients. In contrast to peptides, they found no correlation of delta-T(m) with the identity of the substituting residue but instead observed regular variations in delta-T(m) with the substitution location on different triple helix regions. To relate the delta-T(m) map to peptide-based stability predictions, the authors extracted the activation energy of local helix unfolding from the reported peptide data and constructed the local helix unfolding map and tested it by measuring the hydrogen-deuterium exchange rate for glycine NH residues involved in interchain hydrogen bonds. Makareeva et al. (2008) delineated regional variations in the collagen triple helix stability. Two large, flexible regions deduced from the delta-T(m) map aligned with the regions important for collagen fibril assembly and ligand binding. One of these regions also aligned with a lethal region for Gly substitutions in the alpha-1(I) chain.


Animal Model

Pereira et al. (1993) established a line of transgenic mice that expressed moderate levels of an internally deleted human COL1A1 gene. The gene construct was modeled after a sporadic in-frame deletion that produced a lethal variant of OI. About 6% of the transgenic mice had a lethal phenotype with extensive fractures at birth, and 33% had fractures but were viable. The remaining 61% of the transgenic mice had no apparent fractures as assessed by x-ray examination on the day of birth. Brother-sister matings produced 8 litters in which approximately 40% of the mice had the lethal phenotype, indicating that expression of the transgene was more lethal in homozygous mice. The shortened collagen polypeptide chains synthesized from the human transgene were thought to bind to and produce degradation of the normal collagen genes synthesized from the normal mouse alleles. Khillan et al. (1994) extended these studies using an antisense gene. The strategy of specifically inhibiting expression of a gene with antisense RNA generated from an inverted gene was introduced in 1984 (Izant and Weintraub, 1984; Mizuno et al., 1984; and Pestka et al., 1984). Khillan et al. (1994) assembled an antisense gene that was similar to the internally deleted COL1A1 minigene used by Pereira et al. (1993) except that the 3-prime half of the gene was inverted so as to code for an antisense RNA. Transgenic mice expressing the antisense gene had a normal phenotype, apparently because the antisense gene contained human sequences instead of mouse sequences. Two lines of mice expressing the antisense gene were bred to 2 lines of transgenic mice expressing the minigene. In mice that inherited both genes, the incidence of the lethal fragile bone phenotype was reduced from 92 to 27%. The effect of the antisense gene was directly demonstrated by an increase in the ratio of normal mouse pro-alpha-1(I) chains to human mini-chains in tissues from mice that inherited both genes and had a normal phenotype. The results raised the possibility that chimeric gene constructs that contain intron sequences and in which only the first half of a gene is inverted may be particularly effective as antisense genes.

Pereira et al. (1994) used an inbred strain of transgenic mice expressing a mutated COL1A1 gene to demonstrate interesting features concerning phenotypic variability and incomplete penetrance. These phenomena are striking in families with osteogenesis imperfecta and are usually explained by differences in genetic background or in environmental factors. The inbred strain of transgenic mice expressing an internally deleted COL1A1 gene was bred to wildtype mice of the same strain so that the inheritance of proneness to fracture could be examined in a homogeneous genetic background. To minimize the effects of environmental factors, the phenotype was evaluated in embryos that were removed from the mother one day before term. Examination of stained skeletons from 51 transgenic embryos from 11 separate litters demonstrated that approximately 22% had a severe phenotype with extensive fractures of both long bones and ribs, approximately 51% had a mild phenotype with fractures of ribs only, and approximately 27% had no fractures. The ratio of steady-state levels of the mRNA from the transgene to the level of mRNA from the endogenous gene was the same in all transgenic embryos. The results demonstrated that the phenotypic variability and incomplete penetrance were not explained by variation in genetic background or levels in gene expression. Pereira et al. (1994) concluded from these results that phenotypic variation may be an inherent characteristic of the mutated collagen gene.

Pereira et al. (1998) studied a transgenic model of osteogenesis imperfecta (OI) in mice who expressed a mini-COL1A1 gene containing a large in-frame deletion. Marrow stromal cells from wildtype mice were infused into OI-transgenic mice. In mice that were irradiated with potentially lethal levels or sublethal levels, DNA from the donor marrow stromal cells was detected consistently in marrow, bone, cartilage, and lung at either 1 or 2.5 months after the infusion. The DNA also was detected, but less frequently, in the spleen, brain, and skin. There was a small but statistically significant increase in both collagen content and mineral content of bone 1 month after the infusion. In experiments in which male marrow stromal cells were infused into a female OI-transgenic mouse, fluorescence in situ hybridization assays for the Y chromosome indicated that after 2.5 months, donor male cells accounted for 4 to 19% of the fibroblasts or fibroblast-like cells obtained from primary cultures of the lung, calvaria, cartilage, long bone, tail, and skin. The results supported previous suggestions that marrow stromal cells or related cells in marrow serve as a source for continual renewal of cells in a number of nonhematopoietic tissues.

Aihara et al. (2003) evaluated intraocular pressure (IOP) in transgenic mice with a targeted mutation in the Col1a1 gene and found that the mice had ocular hypertension. The authors suggested an association between IOP regulation and fibrillar collagen turnover.

The mouse mutation 'abnormal gait-2' (Aga2) was identified in an N-ethyl-N- nitrosourea mutagenesis screen. Lisse et al. (2008) identified the Aga2 mutation as a T-to-A transversion within intron 50 of the Col1a1 gene, which introduced a novel 3-prime splice acceptor site that resulted in a frameshift. The mutant protein was predicted to have a novel C terminus that lacked a critical cysteine. Homozygosity for Aga2 was embryonic lethal. Heterozygous Aga2 (Aga2/+) animals showed early lethality, and surviving heterozygotes had widely variable phenotypes that included loss of bone mass, fractures, deformity, osteoporosis, and disorganized trabecular and collagen structures. Abnormal pro-Col1a1 chains accumulated intracellularly in Aga2/+ dermal fibroblasts and were poorly secreted. Intracellular accumulation of Col1a1 was associated with induction of an endoplasmic reticulum stress response and apoptosis characterized by caspase-12 (CASP12; 608633) and caspase-3 (CASP3; 600636) activation in vitro and in vivo.

Chen et al. (2014) reported a mouse model with a heterozygous T-C transition at a splice donor site of the Col1a1 gene, resulting in skipping of exon 9 and a predicted 18-amino acid deletion within the N-terminal region of the triple helical domain (Col1a1(Jrt)/+). Heterozygous mice are smaller than normal and have low bone mineral density and mechanically weak, fracture-prone bones, consistent with an osteogenesis imperfecta phenotype. The number of bone marrow stromal osteoprogenitors was normal, but mineralization was decreased in cultures from the heterozygous mice compared to wildtype mice. The heterozygous mice also had traits associated with Ehlers-Danlos syndrome, including reduced tensile properties of the skin, frayed tail tendon, and, in a third of the mice, noticeable curvature of the spine. The authors noted that this was the first reported animal model of the OI/EDS overlap syndrome.


ALLELIC VARIANTS ( 73 Selected Examples):

.0001 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY97ASP
  
RCV000018825

Byers (1990) provided information about this mutation in osteogenesis imperfecta type II (OI2; 166210).


.0002 OSTEOGENESIS IMPERFECTA, TYPE I

COL1A1, GLY94CYS
  
RCV000018826...

Starman et al. (1989) described a patient with OI type I (OI1; 166200) in whom a population of alpha-1(I) chains had a substitution of cysteine for glycine at position 94.


.0003 OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A1, GLY175CYS
  
RCV000018827...

In a patient with 'moderately severe' OI (OI4; 166220), de Vries and de Wet (1986, 1987) found a substitution of cysteine for glycine-175. Four persons in 3 generations were affected with striking variability in severity of fractures, deformity, and hearing loss, as well as presence or absence of blue sclerae and Wormian bones.


.0004 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY391ARG
  
RCV000018828

Bateman et al. (1987) characterized a structural defect of the alpha-1 chain of type I collagen in a baby with the lethal perinatal form of OI (OI2; 166210). The glycine residue at position 391 had been replaced by arginine. The substitution was associated with increased enzymatic hydroxylation of neighboring regions of the alpha-1 chain. This finding suggested that the sequence abnormality had interfered with the propagation of the triple helix across the mutant region. The abnormal collagen was not incorporated into the more insoluble fraction of bone collagen. The baby appeared to be heterozygous for the sequence abnormality, and, since the parents did not show any evidence of the defect, the authors concluded that the baby had a new mutation. The amino acid substitution could result from a single nucleotide change in the codon GGC (glycine) to produce the codon CGC (arginine).


.0005 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, GLY526CYS
  
RCV000018829...

In a patient with OI type III (OI3; 259420), Starman et al. (1989) identified a population of alpha-1(I) chains in which the glycine at position 526 was replaced by cysteine.


.0006 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY559ASP
  
RCV000018830

Byers (1990) characterized this mutation in a patient with OI type II (OI2; 166210).


.0007 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY673ASP
  
RCV000018831

Byers (1990) described this mutation in a patient with type II OI (OI2; 166210).


.0008 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY667ARG
  
RCV000018832...

This mutation was originally thought to be a substitution of gly664-to-arg in the alpha-1(I) chain, but in fact alters residue 667 from glycine to arginine, according to Byers (1990). Bateman et al. (1988) originally described the mutation in osteogenesis imperfecta type II (OI2; 166210).


.0009 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY691CYS
  
RCV000018833...

Bateman et al. (1988) described this mutation in a patient with type II OI (OI2; 166210).


.0010 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY718CYS
  
RCV000018834

Starman et al. (1989) characterized this mutation in a patient with type II OI (OI2; 166210).


.0011 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY748CYS
  
RCV000018835

In a fetus with severe OI congenita (OI2; 166210), Vogel et al. (1987) found that a single nucleotide change, converting glycine 748 to cysteine in the alpha-1(I) chain, was responsible for destabilizing the triple helix and resulted in the lethal disorder. About 80% of the type I procollagen synthesized by the fibroblasts of the fetus had a decreased thermal stability. The fibroblasts of both parents were normal, indicating that this was a new mutation. Vogel et al. (1988) showed that the procollagen synthesized by the proband's cells is resistant to cleavage by procollagen N-proteinase, a confirmation-sensitive enzyme. Vogel et al. (1988) presented several space-filling models that might explain how the structure of the N-proteinase cleavage site could be affected by an amino acid substitution over 700 amino acid residues away.


.0012 OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A1, GLY832SER
  
RCV000018836

Marini et al. (1989) characterized this mutation in a patient with OI type IV (OI4; 166220). Also see Marini et al. (1993).


.0013 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, GLY844SER
  
RCV000018837...

Pack et al. (1989) described this mutation in a patient with OI type III (OI3; 259420). An unusual biochemical feature of this mutation was normal thermal stability of the intact type I collagen; multiple other mutations in which glycine is replaced result in significantly diminished thermal stability of the type I collagen molecule.


.0014 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY847ARG
  
RCV000018838

Wallis et al. (1990) described this mutation in OI type II (OI2; 166210).


.0015 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY883ASP
  
RCV000018839

Cohn et al. (1990) reported this mutation in a patient with OI type II (OI2; 166210). Recurrence of the OI type II phenotype in this family was explained by the finding of both somatic and germline mosaicism for this mutation in the father of the proband.


.0016 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY904CYS
  
RCV000018840

Constantinou et al. (1989) characterized this mutation in a patient with the perinatal lethal form of OI (OI2; 166210). The mutation caused the synthesis of type I procollagen that was posttranslationally overmodified, secreted at a decreased rate, and had a decreased thermal stability. Constantinou et al. (1990) demonstrated that the proband's mother had the same single base mutation as the proband. However, she had no fractures and no signs of OI except short stature, slightly blue sclerae, and mild frontal bossing; as a child, she had the triangular facies frequently seen in patients with OI. On repeated subculturing, the proband's fibroblasts grew more slowly than the mother's, but they continued to synthesize large amounts of the mutated procollagen in passages 7-14. In contrast, the mother's fibroblasts synthesized decreasing amounts of the mutated procollagen after passage 11. Also, the relative amount of the mutated allele in the mother's fibroblasts decreased with the passage number. In addition, the ratio of the mutated allele to the normal allele in leukocyte DNA from the mother was half the value in fibroblast DNA from the proband. Constantinou et al. (1990) concluded that the simplest interpretation of the findings was that the mother was mildly affected because she was mosaic for the mutation that produced a lethal phenotype in 1 of her 3 children. See also Cohn et al. (1990) and Wallis et al. (1990).


.0017 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY913SER
  
RCV000018841

Byers (1990) described this mutation in OI type II (OI2; 166210).


.0018 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY988CYS
  
RCV000018842

Steinmann et al. (1984) reported the protein abnormality in a cell line established from a patient with OI type II (OI2; 166210). Cohn et al. (1986) characterized the mutation.


.0019 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY1009SER
  
RCV000018843

Byers (1990) characterized this mutation in OI type II (OI2; 166210).


.0020 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, EX22DEL
   RCV000018844

Wallis et al. (1989) described a mutation in COL1A1 resulting in the deletion of exon 22 during RNA processing. The phenotype was progressive deforming OI (OI3; 259420).


.0021 MOVED TO 120150.0022


.0022 OSTEOGENESIS IMPERFECTA

COL1A1, GLY1017CYS
  

Cohn et al. (1988) described a substitution of cysteine for glycine in the carboxy-terminal region of an alpha-1(I) chain in a patient with mild OI. Labhard et al. (1988) studied the same patient and identified the mutation as a heterozygous G-to-T transversion in the COL1A1 gene, resulting in a gly1017-to-cys (G1017C) substitution.

In a patient with 'moderately severe' OI, Steinmann et al. (1986) described an abnormal cysteine residue in cyanogen bromide peptide 6 of an alpha-1(I) chain. According to Byers (1990), the mutation causes substitution of cysteine for gly1017.


.0023 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, 9-BP DEL
   RCV000018847

In a patient with the perinatal lethal form of OI (OI2; 166210), Wallis et al. (1989) described the heterozygous deletion of codons 874-876.


.0024 OSTEOGENESIS IMPERFECTA, TYPE I

COL1A1, FS
  
RCV000018848

Willing et al. (1990) reported a frameshift mutation near the 3-prime end of COL1A1 resulting in the phenotype of OI type I (OI1; 166200).


.0025 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, 1-BP INS, 4088T
   RCV000018849

In a baby with the perinatal lethal form of OI (OI2; 166210), Bateman et al. (1989) identified heterozygosity for insertion of a single uridine nucleotide after basepair 4088 of the prepro-alpha-1(I) mRNA of type I collagen.

Cole et al. (1990) reported further on this patient whose x-ray changes were most consistent with OI IIB (based on an old classification by Sillence et al., 1984; see HISTORY in 166210).


.0026 EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 1

COL1A1, IVS6DS, G-A, -1
  
RCV000018852...

In a girl with Ehlers-Danlos syndrome type VIIA (EDSARTH1; 130060) reported by Cole et al. (1986), Weil et al. (1989) identified a de novo G-to-A transition in the last nucleotide of exon 6 of the COL1A1 gene, resulting in the skipping of exon 6 in the mRNA transcripts. The deleted peptides included those encoding the N-proteinase cleavage site necessary for proper collagen processing. The patient's unaffected parents did not carry the mutation. Further confirmation of the missplicing was obtained by transient expression. The child was born with bilateral dislocation of the hips and knees and mildly hyperelastic skin. At 4 years 7 months, her face had a chubby appearance due to laxity of facial tissues. Height was at the 3rd centile, which was thought to be due in part to progressive right thoracolumbar scoliosis. She also had a large inguinal hernia. Collagen fibrils in the skin were irregular in outline and varied widely in diameter. Cole et al. (1986) had identified a deletion of 24 amino acids (positions 136-159), corresponding to exon 6, from the pro-alpha-1(I) protein (Chu et al., 1984).

D'Alessio et al. (1991) identified the same heterozygous G-to-A mutation in another child with type VII EDS. The mutation resulted in a structural defect in the N terminus of the pro-alpha-1(I) collagen. The G-to-A transition was at the last nucleotide of exon 6 of the COL1A1 gene (which the authors stated corresponded to position -1 of the splice donor site of intron 6, IVS6DS, G-A, -1). The affected allele produced transcripts lacking exon 6 sequences and, in lesser amounts, normally spliced transcripts. The rate of exon 6 skipping was temperature dependent and appeared to decrease substantially when the patient's fibroblasts were incubated at 31 degrees C. The mutation was identical to that described by Weil et al. (1989). This mutation is identical to that found in COL1A2 (120160.0003).


.0027 MOVED TO 120150.0025


.0028 OSTEOGENESIS IMPERFECTA, TYPE I

COL1A1, GLY178CYS
  
RCV000018850

By chemical cleavage of DNA-DNA heteroduplexes, Valli et al. (1991) detected a single basepair mismatch in the COL1A1 gene in a patient with moderately severe osteogenesis imperfecta (OI1; 166200). The mismatch was found in about one-half of the heteroduplex molecules formed between the patient's mRNA and a normal cDNA probe. Sequencing demonstrated a single G-to-T substitution as the first base of the triplet coding for residue 178 of the triple-helical domain of the protein, leading to a glycine-to-cysteine substitution. Allele-specific oligonucleotide (ASO) hybridization to amplified DNA confirmed a de novo point mutation in the proband's genome.


.0029 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY541ASP
  
RCV000018851

.0030 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, GLY154ARG
  
RCV000018853...

In 2 unrelated individuals with a progressive deforming variety of OI (OI3; 259420), Pruchno et al. (1991) found the same new dominant mutation, a substitution of arginine for glycine-154. The mutation occurred at a CpG dinucleotide in a manner consistent with deamination of a methylated cytosine residue. The findings indicated that the type III OI phenotype, previously thought to be inherited in an autosomal recessive manner, can result from new dominant mutations in the COL1A1 gene. Zhuang et al. (1996) found this mutation in a father and his 3 children.


.0031 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY1003SER
  
RCV000018854...

In 2 unrelated infants with perinatal lethal OI (OI2; 166210), Pruchno et al. (1991) observed a de novo dominant mutation that resulted in substitution of serine for glycine-1003. This mutation occurred at a CpG dinucleotide in a manner consistent with deamination of a methylated cytosine residue. Zhuang et al. (1996) found the same mutation in a father and his 3 children. The phenotypes of the patients included manifestations of types I and III/IV osteogenesis imperfecta, but appeared to be milder than the phenotype of the previously described 2 unrelated patients with the G415C mutation. Zhuang et al. (1996) speculated that other mutations in the type I collagen genes, environmental factors, mosaic status of the father, or genes at different loci might be responsible for the variable phenotype. They cited the evidence presented by Aitchison et al. (1988) and by Wallis et al. (1993) from linkage studies, indicating that genes other than the type 1 collagen genes may be involved in causing or modifying OI. The finding that allelic variants of the vitamin D receptor gene (277440) may correlate with low bone density provided another plausible explanation for a more severe phenotype in some individuals with OI due to identical mutations in the genes for type I collagen.


.0032 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY637VAL
  
RCV000018855

In a case of lethal osteogenesis imperfecta (OI2; 166210), Tsuneyoshi et al. (1991) demonstrated substitution of valine for glycine-637.


.0033 OSTEOGENESIS IMPERFECTA, TYPE III/IV

COL1A1, GLY415CYS
  
RCV000018856

In a male in his late 50s with osteogenesis imperfecta thought to be of either type III (OI3; 259420) or type IV (OI4; 166220), Nicholls et al. (1991) described heterozygosity for a substitution of cysteine for glycine at residue 415. Codon 415 was changed from GGC to TGC. The patient's first recorded fracture occurred at 6 weeks of age. Over the next 16 years he suffered more than 270 fractures leading to progressive skeletal deformity. His sclerae were reportedly bluish at birth but had become paler with age--a characteristic of type III OI. He had developed conductive hearing loss in his twenties, a feature not previously described in either type III or type IV. His teeth had been said to have been yellowish brown. The clinical phenotype and the position of the mutation conformed to the prediction of Starman et al. (1989) that the gly-to-cys mutations in the alpha-1(I) chain show a gradient of severity decreasing from the C-terminus to the N-terminus.


.0034 OSTEOGENESIS IMPERFECTA

COL1A1, GLY85ARG
  
RCV000018857

Deak et al. (1991) reported a 56-year-old male with mild osteogenesis imperfecta who underwent surgery for severe aortic valve regurgitation. He was of normal stature, with barrel chest and very pale blue sclera. Radiologic examination showed kyphoscoliosis and multiple compression fractures throughout the dorsal spine, although there was no history of spontaneous fractures. The aortic regurgitation was thought to be part of the connective tissue abnormality. Enlargement of the aortic root and mucinous degeneration of the aortic valve such as were found in this patient had been observed by Weisinger et al. (1975) and others. Deak et al. (1991) demonstrated substitution of arginine for glycine-85 in one of the 2 alpha-1(I) procollagen chains.


.0035 OSTEOGENESIS IMPERFECTA, TYPE IIC

COL1A1, GLY1006VAL
  
RCV000018858

In an infant with perinatal lethal osteogenesis imperfecta of the most severe clinical form, OI IIC (OI2; 166210), with premature rupture of membranes, severe antepartum hemorrhage, stillbirth, severe short-limbed dwarfism, and extreme osteoporosis, Cole et al. (1992) found a glycine-to-valine substitution at residue 1006 in the triple-helical domain of the alpha-1 chain of type I collagen.


.0036 OSTEOGENESIS IMPERFECTA, TYPE IIA

COL1A1, GLY973VAL
  
RCV000018859...

Cole et al. (1992) found substitution of valine for glycine at residue 973 in the triple-helical domain of the alpha-1 chain of type I collagen in an infant born prematurely as a result of premature rupture of membranes and severe antepartum hemorrhage. The infant had the radiographic features of OI IIA (166210).


.0037 OSTEOGENESIS IMPERFECTA, TYPE IIA

COL1A1, GLY256VAL
  
RCV000018860

In an infant with OI IIA (OA2; 166210), Cole et al. (1992) found substitution of valine for glycine at residue 256 in the triple-helical domain of the alpha-1 chain of type I collagen. Severe osteogenesis imperfecta can result from substitutions for glycine as far toward the amino-terminal as position 256. Cole et al. (1992) suggested that the type of glycine substitution which includes, in addition to valine, cysteine, arginine, aspartic acid, serine, alanine, tryptophan, and glutamic acid, and the site and surrounding sequences are probably important factors in determining the severity of the phenotype, i.e., whether it is OI I/IV, OI II, or OI III.


.0038 OSTEOGENESIS IMPERFECTA, TYPE I, MILD

COL1A1, GLY43CYS
  
RCV000018861...

Shapiro et al. (1992) described studies of a woman who at the age of 38, while still premenopausal, was found to have osteopenia, short stature, hypermobile joints, mild hyperelastic skin, mild scoliosis, and blue sclerae (see osteogenesis imperfecta type I, 166200). There was no history of vertebral or appendicular fracture. Hip and vertebral bone mineral density measurements were consistent with marked fracture risk. A basepair mismatch between the proband and control COL1A1 cDNA was detected by chemical cleavage with hydroxylamine:piperidine. Nucleotide sequence analysis demonstrated a G-to-T substitution in codon 43, replacing the expected glycine (GGT) residue with cysteine (TGT). Two of the woman's 4 children were similarly affected.


.0039 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, IVS14DS, G-A, +5
  
RCV000018862

In a fetus with type II OI (166210), Bonadio et al. (1990) demonstrated homozygosity for a G-to-A transition at the moderately conserved +5 position within the splice donor site of the COL1A1 gene. The mutation reduced the efficiency of normal splice site selection since the exon upstream of the mutation was spliced alternatively. The extent of alternative splicing was sensitive to the temperature at which the mutant cells were grown, suggesting that the mutation directly affected spliceosome assembly. The G-to-A transition appeared to be heterozygous at the level of mRNA and protein because it was unable to disrupt completely the normal exon 14 splicing. Bonadio et al. (1990) suggested that low level expression of alternative splicing (as could occur with heterozygous mutation) might be associated with mild dysfunction of connective tissue and perhaps, therefore, a phenotype different from osteogenesis imperfecta. The parents were unrelated and in their thirties at the time of the offspring's conception; neither parent had clinical signs or symptoms of OI. The diagnosis of short-limbed dwarfism was made on the fetus at 5 months of gestation and pregnancy was terminated electively. At autopsy, the fetus had all the characteristics of osteogenesis imperfecta congenita. DNA studies in both parents showed absence of the mutation in all cells studied (Bonadio, 1990). Bonadio (1990) found evidence suggesting uniparental disomy for chromosome 17. A new mutation in 1 parent combined with uniparental disomy would explain the functional homozygosity of the mutation in the fetus. Bonadio (1992) had not had an opportunity to study the possibility further.


.0040 OSTEOGENESIS IMPERFECTA, TYPE I

COL1A1, GLY901SER
  
RCV000018863...

Mottes et al. (1992) identified a GGC (gly) to AGC (ser) transition in codon 901 of the COL1A1 gene in an 8-year-old boy with repeated fractures of both femora. Intramedullar rodding had been performed at the age of 3 years. His mother, 44 years old at the time of his birth, was short (140 cm) and had mild hypoacusis from age 40 and moderate osteoporosis but had never had fractures. The mother was likewise heterozygous for the gly901-to-ser mutation. The mild phenotype was surprising in light of the usual experience that glycine substitutions in the C-terminal region of the collagen triple helix cause lethal OI. The patient was classified as OI type IB on the basis of the absence of dentinogenesis imperfecta (see 166200).


.0041 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY802VAL
  
RCV000018864...

In the surviving child in a family in which the 2 sibs had clinical and radiologic features typical of lethal OI (166210) (Cohen-Solal et al., 1991), Bonaventure et al. (1992) used chemical cleavage of cDNA-RNA heteroduplexes to identify a mismatch in COL1A1 cDNA. The mismatch was subsequently confirmed by sequencing a PCR-amplified fragment and was demonstrated to be due to a G-to-T transversion in the second base of the first codon of exon 41 resulting in the substitution of glycine-802 by valine. The mutation impaired collagen secretion by dermal fibroblasts. The overmodified chains were retained intracellularly. The mutant allele was demonstrated in the mother's leukocytes but not in her fibroblasts, and collagen synthesized by the fibroblasts of both parents was normal. The findings suggested the presence of somatic and germline mosaicism in the phenotypically normal mother, explaining the recurrence of OI.


.0042 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, GLY352SER
  
RCV000018865...

In a 6.5-year-old girl with 'moderately severe OI' (259420), Marini et al. (1993) observed substitution of serine for glycine-352 in the alpha-1 chain of type I collagen. This substitution was produced by a G-to-A transition in 1 allele.


.0043 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, EX15-16DUP
  
RCV000018866

In an infant with the lethal form of osteogenesis imperfecta (166210), Cohn et al. (1993) characterized a tandem duplication mutation within the COL1A1 gene. The structure of the mutation was consistent with unequal crossing over within a 15-bp region of sequence identity between exons 14 and 17. The recombination produced a new 81-bp 17/14 hybrid exon and complete duplication of exons 15 and 16. The sequence implied duplication of 60 amino acid residues within the triple-helical domain with preservation of the Gly-X-Y repeat. The process was thought to mimic that by which the triple-helical domain of fibrillar collagen genes arose in evolution by repeated tandem duplication of an ancestral unit exon.


.0044 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY415SER
  
RCV000018867...

In a female infant who died in her first hour of life because of respiratory failure and showed the features of severe osteogenesis imperfecta thought to fall between type II (166210) and type III (259420) of Sillence, Mottes et al. (1993) demonstrated by chemical cleavage of mismatched bases and subsequent sequencing a G-to-A transition that caused substitution of gly415 with serine. The same mutation was found in the clinically normal father's spermatozoa and lymphocytes. Mosaicism in the father's germline explained the occurrence in the family of 2 later pregnancies in which OI was documented by radiographs and ultrasound investigations.


.0045 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY565VAL
  
RCV000018868

In an infant with osteogenesis imperfecta type IIA (166210) born of a 37-year-old mother and a 39-year-old father, Mackay et al. (1993) mapped the defect in type I collagen to alpha-1 cyanogen bromide peptide 7, a region corresponding to 271 amino acid residues of either the alpha-1 or the alpha-2 chain of type I collagen. Polymerase chain reaction amplification of the corresponding region of the alpha-1(I) mRNA followed by SSCP analysis of restriction enzyme digests of the PCR products allowed further mapping of the mutation to a small region of the COL1A1 gene. A heterozygous G-to-T transversion within the last splicing codon of exon 32 was identified by DNA sequence analysis. This mutation had resulted in the substitution of glycine-565 by a valine residue. The mutation was shown to have occurred de novo.


.0046 OSTEOGENESIS IMPERFECTA, TYPE I

COL1A1, IVS26DS, G-A, +1
  
RCV000490727...

Stover et al. (1993) demonstrated defective splicing of mRNA from one COL1A1 allele in a patient with mild type I OI (166200). Genovese et al. (1989) had demonstrated that dermal fibroblasts from this patient showed a novel species of COL1A1 mRNA in the nuclear compartment of cells; that it was not collinear with a cDNA probe, and, therefore, with the fully spliced COL1A1 mRNA, was indicated by indirect RNase protection assays. Stover et al. (1993) showed that a G-to-A transition in the first position of the donor site of intron 26 resulted in the inclusion of the entire sequence in the mature mRNA that accumulated in the nuclear compartment. The retained intron contained an in-frame stop codon and introduced an out-of-frame insertion within the collagen mRNA producing stop codons downstream of the insertion. These changes probably accounted for the failure of the mutant RNA to appear in the cytoplasm. Unlike other splice site mutations within collagen mRNA that resulted in exon skipping and a truncated but in-frame RNA transcript, this mutation did not result in production of a defective COL1A1 chain. Instead, the mild nature of the disease in this patient reflected failure to process a defective mRNA and, thus, the absence of a protein product from the mutant allele.


.0047 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY355ASP
  
RCV000018870

Raghunath et al. (1994) developed a method for early prenatal diagnosis of molecular disorders involving types I and III collagens. The method took advantage of the fact that isolated chorionic villi contain significant amounts of collagen in their extracellular matrix and synthesize collagens in vitro. They correctly predicted a healthy fetus and an embryo affected with lethal osteogenesis imperfecta (166210) in consecutive pregnancies from a couple in which the asymptomatic mother was a somatic mosaic for a COL1A1 G-to-A transition resulting in substitution of glycine-355 by aspartic acid. Steinmann (1994) stated that this is the sixth gly-to-asp substitution in the alpha-1(I) chain, all of which have been associated with lethal OI regardless of position of the mutation. This was, furthermore, the ninth example of molecularly proven mosaicism. The asymptomatic mother was 153 cm tall and was shorter by 12 to 22 cm than her female first-degree relatives.


.0048 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, GLY862SER
  
RCV000018871...

Namikawa et al. (1995) identified a heterozygous gly862-to-ser substitution in 2 sibs with type III osteogenesis imperfecta (259420). The mutation was also detected in various paternal tissues; the mutant allele accounted for approximately 11% of the COL1A1 alleles in blood, 24% of those in fibroblasts, and 43% of those in sperm. The father was phenotypically normal. The parents were nonconsanguineous. The first-born child died of respiratory failure at age 3 years after repeated hospital admissions for recurrent fractures and respiratory insufficiency. The second-born child was identified as having OI by ultrasonography at 32 weeks' gestation on the basis of angulated femoral bones. The father had no history of fractures or other indications of connective tissue disease. His height was 173 cm (73th percentile for a 30- to 39-year-old Japanese male) and he was taller than his father. His weight was at the 62nd percentile. Skin, joints, sclera, and teeth were normal. Germline mosaicism was obviously responsible for the recurrence. Namikawa et al. (1995) pointed out that there is a cluster of gly-to-ser substitutions associated with nonlethal phenotypes (gly832-to-ser, gly844-to-ser, and gly901-to-ser (120150.0040), with gly862-to-ser in the middle) and that this nonlethal cluster is located between 2 lethal clusters.


.0049 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, GLY661SER
  
RCV000018872...

Nuytinck et al. (1996) observed this mutation in a severely affected infant with type III OI (259420). The same mutation in the COL1A2 gene (120160.0030) results in a much milder phenotype, namely post menopausal osteoporosis.


.0050 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, LEU-PRO, C-TER PROPEPTIDE
  
RCV000018873...

Oliver et al. (1996) described unusual molecular findings in a young girl who presented with severe type III OI (259420). Her otherwise healthy mother had pale blue sclerae and recurrent joint dislocations of the ankles, shoulders, knees, elbows, wrists, and neck from 8 years of age. She suffered dislocation of the left hip during the pregnancy. The maternal grandfather was 177 cm tall and had recurrent dislocations of the right elbow and right knee since age 10 years. He had pale blue sclerae from childhood. He developed progressive deafness of the left ear, and later Meniere disease. The proposita had dark blue sclerae and multiple old and new fractures at birth. Subsequently she suffered at least 200 fractures, mostly of the femurs. At 3 years of age the sclerae were pale blue. There was a severe pectus carinatum. The skin was abnormally soft, and there was marked generalized joint laxity. The broad forehead and triangular shaped face were typical of OI. Teeth and hearing were normal and she did not bruise easily. Skin fibroblast cultures from the child produced both normal and posttranslationally overmodified type I collagen. Cyanogen bromide peptide maps of the abnormal protein indicated a C-terminal mutation. Examination of the C-propeptide sequences demonstrated 2 heterozygous single base changes in the child. One, an A-to-C transversion changing threonine to proline at residue 29 of the COL1A2 C-propeptide, was also present in the mother and maternal grandfather but not in 50 unrelated controls. The second mutation, a T-to-C transition, altered the last amino acid residue of the COL1A1 C-propeptide from leucine to proline and had occurred de novo in the affected child. The latter mutation was thought to be responsible for OI. Oliver et al. (1996) stated that the most frequent cause of excess posttranslational modification of collagens is the substitution of glycine in 1 Gly-X-Y repeat unit of the triple helix. No such mutation was detected in the proband. They commented that the change in the COL1A2 gene may have been related to the connective tissue manifestations in the mother and maternal grandfather.


.0051 BONE MINERAL DENSITY VARIATION QUANTITATIVE TRAIT LOCUS

COL1A1, IVS1, 2046G-T (rs1800012)
  
RCV000018874

Screening the COL1A1 transcriptional control regions by PCR-SSCP in a sample of 50 subjects, Grant et al. (1996) found 3 polymorphisms in the first intron, 2 of which were rare (allele frequency approximately 4% and 3%) and 1 common (allele frequency approximately 22%). The common polymorphism was characterized as a G-to-T substitution at the first base of a consensus site for the transcription factor Sp1 (189906) in the first intron of COL1A1 (nucleotide 2046). Grant et al. (1996) devised a PCR-based screen and studied allele distribution in 2 populations of British women, 1 in Aberdeen and 1 in London. They found that the G/T polymorphism was significantly related to bone mass and osteoporotic fracture (166710). G/T heterozygotes had significantly lower bone mineral density (BMD) than G/G homozygotes (SS) in both populations, and BMD was lower still in G/T homozygotes (ss). The unfavorable Ss and ss genotypes were over-represented in patients with severe osteoporosis and vertebral fractures (54%), as compared with controls (27%) equivalent to a relative risk of 2.97 for vertebral fracture in individuals who carried the 's' allele. These results were confirmed and extended by Uitterlinden et al. (1998).

Uitterlinden et al. (1998) studied the Sp1-binding site polymorphism in 1,778 postmenopausal women in the Netherlands and found that compared with the 1,194 women with the SS genotype, the 526 women with the Ss genotype had 2% lower bone mineral density at the femoral neck (p = 0.003) and the lumbar spine (p = 0.02); the 58 women with the ss genotype had reductions of 4% at the femoral neck (p = 0.05) and 6% at the lumbar spine (p = 0.005). These differences increased with age. Women with the Ss and ss genotypes were overrepresented among the 111 women who had incident nonvertebral fractures.

Uitterlinden et al. (2001) studied the interaction between polymorphisms of the vitamin D receptor gene (VDR; 601769) and the Sp1-binding site polymorphism of COL1A1 and concluded that interlocus interaction is likely to be an important component of osteoporotic fracture risk.

Sainz et al. (1999) studied the Sp1-binding site polymorphism and measurements of the size and the density of vertebral bone in 109 healthy prepubertal girls. On average, 22 girls with the Ss genotype and 1 girl with the ss genotype had 6.7% and 33.2% lower cancellous bone density in the vertebrae, respectively, than girls with the SS genotype. In contrast, there was no association between the size of the vertebrae and the COL1A1 genotypes. (One of the authors (Gilsanz, 2008) noted that the correct ss genotype figure is 33.2% rather than the 49.4% cited in the 1999 article.)

In an association study involving 3,270 women enrolled in an osteoporosis screening program, Stewart et al. (2006) analyzed 3 SNPs in the promoter and intron 1 of the COL1A1 gene (the Sp1-binding site polymorphism rs1800012, which they designated +1245G/T; rs1107946, and rs2412298) and their haplotypes. The polymorphisms were in strong linkage disequilibrium and 3 haplotypes accounted for more than 95% of the alleles at the COL1A1 locus. Homozygote carriers of 'haplotype 2' had reduced BMD, whereas homozygote carriers of 'haplotype 3' had increased BMD. Stewart et al. (2006) concluded that there is bidirectional regulation of BMD by the 2 haplotypes in the 5-prime flank of COL1A1.

In a case-control study of 206 Caucasians with otosclerosis (see 166800) and 282 Caucasian controls, Chen et al. (2007) identified 2 haplotypes, composed of 5 SNPs in the COL1A1 gene (rs1800012, rs9898186, rs2269336, rs11327935, and rs1107946), that were significantly associated with otosclerosis. In osteoblast cell lines, the protective H2 haplotype decreased promoter activity, whereas the susceptibility H3 haplotype increased promoter activity by affecting binding of transcription factors to cis-acting elements, suggesting that increased amounts of collagen alpha-1 homotrimers are causally related to the development of otosclerosis. Consistent with this hypothesis, Chen et al. (2007) demonstrated hearing loss in mice from a naturally occurring mutant strain that only deposits homotrimeric type I collagen. The authors designated the Sp1-binding site polymorphism, rs1800012, as +1126G/T.

Jin et al. (2009) showed that the previously reported 5-prime untranslated region (UTR) SNPs in the COL1A1 gene (-1997G-T, rs1107946, 120150.0067; -1663indelT, rs2412298, 120150.0068; +1245G-T, rs1800012) affected COL1A1 transcription. Transcription was 2-fold higher with the osteoporosis-associated G-del-T haplotype compared with the common G-ins-G haplotype. The region surrounding rs2412298 recognized a complex of proteins essential for osteoblast differentiation and function including NMP4 (ZNF384; 609951) and Osterix (SP7; 606633), and the osteoporosis-associated -1663delT allele had increased binding affinity for this complex. Further studies showed that haplotype G-del-T had higher binding affinity for RNA polymerase II, consistent with increased transcription of the G-del-T allele, and there was a significant inverse association between carriage of G-del-T and bone mineral density (BMD) in a cohort of 3,270 Caucasian women. Jin et al. (2009) concluded that common polymorphic variants in the 5-prime UTR of COL1A1 regulate transcription by affecting DNA-protein interactions, and that increased levels of transcription correlated with reduced BMD values in vivo by altering the normal 2:1 ratio between alpha-1(I) and alpha-2(I) chains.


.0052 OSTEOGENESIS IMPERFECTA, TYPE I, MILD

COL1A1, GLY13ALA
  
RCV000018875...

Mayer et al. (1996) described a G-to-C transversion in 1 COL1A1 allele resulting in a gly13-to-ala substitution in the triple-helical domain of the pro-alpha-1(I) collagen chain. The mutation was found in a 35-year-old woman with a mild form of osteogenesis imperfecta type I (166200) who presented with spontaneous dissection of the right internal carotid artery and the right vertebral artery after scuba diving but without obvious head or neck trauma. Other than a history of easy bruising and bluish sclerae, she had no evidence of a connective tissue disorder. There had been no bone fractures or dental problems nor was there family history of vasculopathy.


.0053 OSTEOGENESIS IMPERFECTA, TYPE II, THIN-BONE TYPE

COL1A1, TRP94CYS
  
RCV000018876

Cole et al. (1996) described an infant with lethal perinatal osteogenesis imperfecta (166210) resulting from the substitution of trp94 by cysteine (Y94C) in the C-terminal propeptide of the pro-alpha-1(I) chain. The infant was born at 38 weeks' gestation with numerous fractures of the limbs, skull, and ribs, and with subarachnoid and subdural hemorrhages. Death from respiratory distress occurred within hours of birth. The limbs and torso were of normal length, shape, and proportion. All bones were relatively normal in shape and the long bones showed normal metaphyseal modeling. These clinical and radiographic features were similar to those observed in another baby with OI II resulting from a mutation of the C-terminal propeptide of the pro-alpha-1 chains (Bateman et al., 1989; Cole et al., 1990), but dissimilar from those reported in babies with OI II resulting from helical mutations of type 1 collagen. Cole et al. (1996) stated that the infant's Y94C mutation disturbed procollagen folding and retarded the formation of disulfide-linked trimers. The endoplasmic reticulum resident molecular chaperone BiP, which binds to malfolded proteins, was induced and bound to type I procollagen produced by the OI fibroblasts. Unassembled mutant pro-alpha-1 chains were also retained in the rough endoplasmic reticulum.


.0054 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, 562-BP DEL
  
RCV000018877

Wang et al. (1996) identified a novel multiexon deletion in a COL1A1 allele. They examined a 9-year-old girl and her 37-year-old father, both affected with severe OI type III (259420). SSCP and PCR were used to identify a 562-bp deletion extending from the last 3 nucleotides of exon 34 to 156 nucleotides from the 3-prime end of intron 36. This deletion was also detected in the clinically normal grandmother, who was confirmed to be a mosaic carrier. Three alternative forms of mutant mRNA resulted from this deletion. One form had a deletion with end points identical to the genomic deletion, resulting in an in-frame mutant mRNA. The second in-frame form used the normal exon 32 splice donor and the exon 37 acceptor. The out-of-frame third form used a cryptic donor site in exon 34 and the exon 37 acceptor site. Although the in-frame forms of mRNA constituted 60% of the mRNA, no mutant protein was detected in cultured fibroblasts or in cultured osteoblasts of the patients.

Cabral and Marini (2004) examined a mosaic carrier in the family previously reported by Wang et al. (1996), the mother of the 'father.' She was 67 years old when she died of pneumonia after an intracranial hemorrhage. Two of her 7 children had severe OI type III. One affected son died of pneumonia as a child. On physical examination, the mosaic carrier had normal height (161 cm; 50th percentile for adult women) and well-proportioned span. The only manifestations of a connective tissue disorder were blue sclerae and a triangular-shaped facies. She had never sustained a fracture. Bone histology was normal. Thus, in OI, substantially normal skeletal growth, density, and histology are compatible with a 40 to 75% burden of osteoblasts heterozygous for a COL1A1 mutation. These data were considered encouraging for mesenchymal stem cell transplantation, since mosaic carriers are a naturally occurring model for cell therapy.


.0055 OSTEOGENESIS IMPERFECTA, TYPE I

COL1A1, ARG963TER
  
RCV000018878...

Korkko et al. (1997) found that 2 unrelated patients with type I osteogenesis imperfecta (166200) had identical mutations that converted the codon for arginine-963 from CGA to TGA (stop). Willing et al. (1994) also reported this nucleotide change in a patient with type 1 OI.


.0056 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY586VAL
  
RCV000018879

Forlino et al. (1994) described type III OI in a patient with a G586V substitution in the alpha-2 chain of collagen I (120160.0023). Lund et al. (1997) described the same mutation, a G586V substitution, in the alpha-1 chain in a case of lethal OI type II (166210). They presented this as evidence that, perhaps because there are 2 alpha-1 chains and 1 alpha-2 chain in type I collagen, substitutions in the alpha-1 gene have more serious consequences. They pointed out that identical biochemical alterations in the same chain are known to have different phenotypic effects, both within families and between unrelated patients.


.0057 EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 1

COL1A1, IVS5AS, G-A, -1
  
RCV000018880

In a girl with arthrochalasia-type Ehlers-Danlos syndrome (EDSARTH1; 130060), born of a 23-year-old Caucasian father and a 31-year-old mother of Japanese origin, Byers et al. (1997) identified a heterozygous G-to-A transition at position -1 of the splice acceptor site of intron 5 of the COL1A1 gene, resulting in the skipping of exon 6. She presented at birth with large fontanels, a small umbilical hernia, joint laxity, contractures of the digits of both hands, short femurs, pendulous skin folds, and bilateral hip dislocation. PCR amplification around exon 6 of the alpha-1 cDNA produced 3 bands, one of a normal size, a second about 15 to 20 bp smaller, and a third equivalent to the product expected with deletion of the sequence of the entire exon 6. The sequence of the smaller band indicated that there was a deletion of 15 bp encoding 5 amino acids (asn-phe-ala-pro-gln), which included the pepsin-sensitive site (phe-ala) and the N-proteinase cleavage site (pro-gln).


.0058 OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A1, IVS8DS, G-A, +1
  
RCV000018882

Schwarze et al. (1999) reported a patient thought to have moderately severe osteogenesis imperfecta type IV (166220). Between ages 10 months and 9 years, she sustained several dozen spontaneous fractures to the bones of her legs, hands, and feet. After age 9 years, the fracture frequency decreased dramatically. At this point, she was growth retarded, with a height of 112 cm, which corresponded to her adult height. Her virtual cessation of growth was attributed, in part, to progressive scoliosis and moderate deformity of her lower limbs. Her mobility was reduced, and she spent most of her time in a wheelchair. Her sclerae remained grayish-blue. In this patient, Schwarze et al. (1999) identified a G-to-A transition at the +1 position of intron 8 of the COL1A1 gene. They stated that most splice site mutations lead to a limited array of products, including exon skipping, use of cryptic splice acceptor or donor sites, and intron inclusion. In the patient reported by Schwarze et al. (1999), however, the splice site mutation resulted in the production of several splice products from the mutant allele. These included 1 in which the upstream exon 7 was extended by 96 nucleotides, others in which either intron 8 or introns 7 and 8 were retained, 1 in which exon 8 was skipped, and 1 that used a cryptic donor site in exon 8. To determine the mechanism by which exon 7 redefinition might occur, Schwarze et al. (1999) examined the order of intron removal in the region of the mutation by using intron/exon primer pairs to amplify regions of the precursor nuclear mRNA between exon 5 and exon 10. Removal of introns 5, 6, and 9 was rapid. Removal of intron 8 usually preceded removal of intron 7 in the normal gene, although, in a small proportion of copies, the order was reversed. The proportion of abnormal products suggested that exon 7 redefinition, intron 7 plus intron 8 inclusion, and exon 8 skipping all represented products of the impaired rapid pathway, whereas the intron 8 inclusion product resulted from use of the slow intron 7-first pathway. The very low-abundance cryptic exon 8 donor site product could have arisen from either pathway. Schwarze et al. (1999) interpreted the results as suggesting that there is commitment of the pre-mRNA to the 2 pathways, independent of the presence of the mutation, and that the order and rate of intron removal are important determinants of the outcome of splice site mutations and may explain some unusual alterations.


.0059 EHLERS-DANLOS SYNDROME, CLASSIC TYPE

COL1A1, ARG134CYS
  
RCV000018884...

In 2 unrelated patients with classic Ehlers-Danlos syndrome (see 130000), Nuytinck et al. (2000) found the same mutation in the COL1A1 gene. The first patient was a 5-year-old girl who had been born near term, after premature rupture of membranes. She had a history of easy bruising and scarring after minimal trauma and presented soft velvety, and hyperextensible skin. In addition, she had atrophic paper scars on the face, elbows, knees, and shins; ecchymoses on the lower legs; and generalized joint hyperlaxity. Her facial appearance, which included redundant skin folds on the eyelids and very soft earlobes, was reminiscent of classic EDS. The sclerae were white, and x-ray examination indicated that she had no signs of osteoporosis. The second patient was a 7-year-old boy who had been born near term and showed hypotonia in the first month of life. An operation was performed for strabismus. When examined at the age of 5 years, he had typical features of classic EDS, including soft and doughy skin, moderate skin hyperextensibility, and joint hyperlaxity. In addition, he had a pronounced tendency for splitting of the skin, easy bruising, and impaired wound healing. He also presented an unusual tenderness of the skin and soft tissues, evident when he was touched. He had pectus excavatum and flat feet. The sclerae were white, and radiographic examination showed no signs of osteoporosis. Both patients had an arg134-to-cys substitution in the COL1A1 gene. The arginine residue was highly conserved and localized to the X position of the Gly-X-Y triplet. As a consequence, intermolecular disulfide bridges were formed, resulting in type I collagen aggregates, which were retained in cells. Whereas substitutions of glycine residues in type I collagen invariably result in osteogenesis imperfecta, substitutions of nonglycine residues in type I collagen had not previously been associated with a human disease. In contrast, arg-to-cys substitutions in type II collagen had been identified in a variety of chondrodysplasias (e.g., see 120140.0003, 120140.0016, 120140.0018, 120140.0029).


.0060 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, 9-BP DUP
  
RCV000414247...

Cabral et al. (2003) studied the effect of shifting the register of the collagen helix by a single Gly-X-Y triplet on collagen assembly, stability, and incorporation into fibrils and matrix. The studies utilized a triplet duplication in exon 44 of the COL1A1 gene that occurred in the cDNA and genomic DNA of 2 sibs with lethal OI type II (166210). The normal allele encodes 3 identical glycine-alanine-hydroxyproline (gly-ala-hyp) triplets at amino acids 868-876, whereas the mutant allele encodes 4. The register shift delayed helix formation, causing overmodification. Cabral et al. (2003) showed that N-propeptide cleavage in procollagen with the triplet duplication was slower than normal, indicating that the register shift persisted through the entire helix. The register shift also disrupted incorporation of mutant collagen into fibrils and matrix. The profound effects of shifting on chain interaction in the helix and on fibril formation correlated with the severe clinical consequences. The probands were the male and female offspring of healthy parents in their twenties. The mother was entirely normal by clinical history and physical examination but was shown to be a mosaic carrier with a low percentage of heterozygous mutant fibroblasts and leukocytes (10 and 15%, respectively).


.0061 OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A1, 3-BP DEL, 1964GGC
  
RCV000018886

In a family in which the mother and 4 children were affected with autosomal dominant osteogenesis imperfecta type IV (166220), Lund et al. (1996) identified an in-frame deletion of nucleotides 1964-1966 (GGC) from a series of 6 nucleotides (GAG/GCT) encoding codons 437 and 438 in exon 27 of the COL1A1 gene, resulting in the removal of an alanine residue at position 438 and a glu437-to-asp (E437D) substitution in the alpha-1 (I) collagen chain. The father was clinically normal and lacked the mutation, which was detected by restriction enzyme analysis in all affected family members. Clinical variation among affected members was considerable; the most consistent clinical features were reduced height and extraosseous manifestations of OI. The mother was 136 cm tall and her 19-year-old daughter 132 cm tall. A 28-year-old son was 137 cm tall but a 24-year-old son was 162 cm tall and a 31-year-old daughter 151 cm tall. All had white sclerae and dentinogenesis imperfecta. The heights of the mother, 2 daughters (31 and 19 years of age), and 2 sons (28 and 24 years of age), were 136, 151, 132, 137, and 162 cm, respectively. The mother and eldest sib had otosclerosis. The 24-year-old son was physically active and capable in sports, including contact sports, and his OI diagnosis was questioned by other members of the family.


.0062 OSTEOGENESIS IMPERFECTA, TYPE I

OSTEOGENESIS IMPERFECTA, TYPE IV, INCLUDED
COL1A1, IVS19DS, G-C, +1
  
RCV000018887...

Cabral and Marini (2004) described a family in which the mother was a mosaic carrier of an IVS19DS+1G-C mutation in the COL1A1 gene and had a phenotype compatible with OI type I (166200), whereas her 2 sons had moderately severe OI type IV (166220).


.0063 CAFFEY DISEASE

COL1A1, ARG836CYS
  
RCV000018889...

In affected individuals and obligate carriers from 3 unrelated families with Caffey disease (CAFYD; 114000), Gensure et al. (2005) identified heterozygosity for a 3040C-T transition in exon 41 of the COL1A1 gene, predicted to result in an arg836-to-cys (R836C) substitution within the triple-helical domain of the alpha-1 chain of type I collagen. None of the affected individuals or obligate carriers in any of the families had clinical signs of osteogenesis imperfecta, although some individuals did have joint hyperlaxity and hyperextensible skin. In 1 family the mutation was not found in the unaffected father, and in another family it was not found in the unaffected parents or sib of affected monozygotic twins in whom the mutation was assumed to have arisen de novo.

In 5 affected members of a Thai family with Caffey disease, Suphapeetiporn et al. (2007) identified heterozygosity for the R836C mutation in the COL1A1 gene.

Kamoun-Goldrat et al. (2008) identified heterozygosity for the R836C mutation in the COL1A1 gene in the pulmonary tissue of a fetus with a severe form of prenatal cortical hyperostosis from a terminated pregnancy at 30 weeks' gestation. The authors speculated that mutation in another gene might have also been involved.


.0064 COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 1

COL1A1, GLY13ASP
  
RCV000018891

In a patient wth combined osteogenesis imperfecta and Ehlers-Danlos syndrome (OIEDS1; 619115), Cabral et al. (2005) identified a gly13-to-asp (G13D) mutation in the COL1A1 gene. The authors showed that the disorder in this patient and 6 additional patients with a similar phenotype was due to glycine substitutions or an amino acid deletion within the N-anchor domain. Mutations within this stabilizing domain induced its reversible unfolding above 34 degrees centigrade (Makareeva et al., 2006).


.0065 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, GLY76GLU
  
RCV000018892

In a 13-year-old girl with severe osteogenesis imperfecta type III (OA3; 259420), Cabral et al. (2001) identified heterozygosity for a 761G-A transition in exon 11 of the COL1A1 gene, resulting in a gly76-to-glu (G76E) substitution. The mutant collagen helices have altered folding, and thermal denaturation curves demonstrated a decrease in helix stability. Cabral et al. (2001) stated that this was the first report of a glutamic acid substitution in the alpha-1(I) chain causing nonlethal osteogenesis imperfecta.


.0066 EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 1

COL1A1, IVS5AS, A-T, -2
  
RCV000018893

In a girl with severe arthrochalasia-type Ehlers-Danlos syndrome (EDSARTH1; 130060), Giunta et al. (2008) identified a heterozygous A-to-T transversion in the splice acceptor site of intron 5 of the COL1A1 gene, resulting in the skipping of exon 6. The mutation resulted in the deletion of amino acids from the N-proteinase cleavage site. The patient had bilateral hip dislocation, multiple subluxations of shoulders, elbows, and knees, arthrogryposis, clubfoot, and hypotonia.


.0067 BONE MINERAL DENSITY VARIATION QUANTITATIVE TRAIT LOCUS

COL1A1, 5-PRIME UTR, G-T, -1997 (rs1107946)
  
RCV000018881

.0068 BONE MINERAL DENSITY VARIATION QUANTITATIVE TRAIT LOCUS

COL1A1, 5-PRIME UTR, INDEL T, -1663 (rs2412298)
  
RCV000018883

.0069 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, 1-BP DEL, 4247C
  
RCV000034354

Takagi et al. (2011) reported a sporadic case of what they termed 'classic OI IIC' (see 166210) in a Japanese patient in whom they identified a 1-bp deletion (4247delC) in the C-propeptide region of the COL1A1 gene, resulting in a frameshift.


.0070 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, ALA1387VAL
  
RCV000034355

In 2 Japanese sibs with features of 'OI IIC' (see 166210) but less distortion of the tubular bones (OI dense bone variant), Takagi et al. (2011) identified a 4160C-T transition in the C-propeptide region of the COL1A1 gene, resulting in an ala1387-to-val (A1387V) substitution. Familial gene analysis revealed somatic mosaicism of the mutation in the clinically unaffected father of the sibs, whereas their mother and healthy older sister did not have the mutation.


.0071 COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 1

COL1A1, ARG888CYS
  
RCV000485287...

In 4 patients in a small pedigree with combined osteogenesis imperfecta and Ehlers Danlos syndrome-1 (OIEDS1; 619115), Cabral et al. (2007) identified heterozygosity for a c.3196C-T transition (c.3196C-T, NM_000088.3) in the COL1A1 gene, resulting in an arg888-to-cys (R1066C) substitution in the Y position of one of the Gly-X-Y triplets that compose the collagen helix. The substitution in the Y position was shown to result in less delay in helix formation than would have been expected for a glycine substitution. Disulfide-bonded dimers of alpha(I) chains formed inefficiently in helices with 2 mutant chains; however, secretion from cells was normal. Formation of disulfide dimers at position 888 resulted in helix kinking, with resulting decreased helix stability and propagation of altered secondary structure along the remaining helix.


.0072 COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 1

COL1A1, GLY188ASP
  
RCV000490656...

In a patient with combined osteogenesis imperfecta and Ehlers Danlos syndrome-1 (OIEDS1; 619115), Malfait et al. (2013) identified a heterozygous c.563A-G transition (c.563A-G, NM_000088.3) in exon 7 of the COL1A1 gene, resulting in a gly188-to-asp (G188D) substitution.


.0073 OSTEOGENESIS IMPERFECTA, TYPE II

COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 1, INCLUDED
COL1A1, 9-BP DEL, NT3150
  
RCV000413092...

Osteogenesis Imperfecta, Type II

In an infant with lethal osteogenesis imperfecta type II (OI2; 166210), Hawkins et al. (1991) identified a 9-bp deletion in the COL1A1 gene, which was not present in the parents. The mutation was said to occur within a repeating sequence of exon 43, causing the loss of 1 of 3 consecutive gly-ala-pro triplets at positions 868-876, but does not disrupt the Gly-X-Y sequence.

Combined Osteogenesis Imperfecta and Ehlers-Danlos Syndrome 1

In a patient with combined osteogenesis imperfecta and Ehlers-Danlos syndrome-1 (OIEDS1; 619115), Symoens et al. (2017) identified a heterozygous in-frame 9-bp deletion (c.3150_3158del) in exon 44 of the COL1A1 gene, resulting in deletion of 3 amino acids (Ala1053_Gly1055del). This mutation was seen in 9% of DNA derived from patient fibroblasts and in none of the DNA derived from blood. Symoens et al. (2017) stated that this was the same mutation identified by Hawkins et al. (1991) in a patient with lethal OI and concluded that mosaicism might have been responsible for the mild symptoms in their patient.


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  146. Willing, M. C., Deschenes, S. P., Scott, D. A., Byers, P. H., Slayton, R. L., Pitts, S. H., Arikat, H., Roberts, E. J. Osteogenesis imperfecta type I: molecular heterogeneity for COL1A1 null alleles of type I collagen. Am. J. Hum. Genet. 55: 638-647, 1994. [PubMed: 7942841, related citations]

  147. Willing, M. C., Deschenes, S. P., Slayton, R. L., Roberts, E. J. Premature chain termination is a unifying mechanism for COL1A1 null alleles in osteogenesis imperfecta type I cell strains. Am. J. Hum. Genet. 59: 799-809, 1996. [PubMed: 8808594, related citations]

  148. Willing, M. C., Pruchno, C. J., Atkinson, M., Byers, P. H. Osteogenesis imperfecta type I is commonly due to a COL1A1 null allele of type I collagen. Am. J. Hum. Genet. 51: 508-515, 1992. [PubMed: 1353940, related citations]

  149. Willing, M. C., Pruchno, C. J., Byers, P. H. Molecular heterogeneity in osteogenesis imperfecta type I. Am. J. Med. Genet. 45: 223-227, 1993. [PubMed: 8456806, related citations] [Full Text]

  150. Willing, M. C., Slayton, R. L., Pitts, S. H., Deschenes, S. P. Absence of mutations in the promoter of the COL1A1 gene of type I collagen in patients with osteogenesis imperfecta type I. J. Med. Genet. 32: 697-700, 1995. [PubMed: 8544188, related citations] [Full Text]

  151. Zhuang, J., Constantinou, C. D., Ganguly, A., Prockop, D. J. A single base mutation in type I procollagen (COL1A1) that converts glycine alpha(1)-541 to aspartate in a lethal variant of osteogenesis imperfecta: detection of the mutation with a carbodiimide reaction of DNA heteroduplexes and direct sequencing of products of the PCR. Am. J. Hum. Genet. 48: 1186-1191, 1991. [PubMed: 2035536, related citations]

  152. Zhuang, J., Tromp, G., Kuivaniemi, H., Castells, S., Prockop, D. J. Substitution of arginine for glycine at position 154 of the alpha-1 chain of type I collagen in a variant of osteogenesis imperfecta: comparison to previous cases with the same mutation. Am. J. Med. Genet. 61: 111-116, 1996. [PubMed: 8669434, related citations] [Full Text]


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* 120150

COLLAGEN, TYPE I, ALPHA-1; COL1A1


Alternative titles; symbols

COLLAGEN OF SKIN, TENDON, AND BONE, ALPHA-1 CHAIN


Other entities represented in this entry:

COL1A1/PDGFB FUSION GENE, INCLUDED

HGNC Approved Gene Symbol: COL1A1

SNOMEDCT: 1197018005, 205496008, 205497004, 24752008, 254110009, 385482004, 385483009, 7134007, 715318006, 78314001;   ICD10CM: M89.8, Q78.0, Q79.61;   ICD9CM: 756.51;  


Cytogenetic location: 17q21.33     Genomic coordinates (GRCh38): 17:50,184,101-50,201,631 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
17q21.33 {Bone mineral density variation QTL, osteoporosis} 166710 Autosomal dominant 3
Caffey disease 114000 Autosomal dominant 3
Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 619115 Autosomal dominant 3
Ehlers-Danlos syndrome, arthrochalasia type, 1 130060 Autosomal dominant 3
Osteogenesis imperfecta, type I 166200 Autosomal dominant 3
Osteogenesis imperfecta, type II 166210 Autosomal dominant 3
Osteogenesis imperfecta, type III 259420 Autosomal dominant 3
Osteogenesis imperfecta, type IV 166220 Autosomal dominant 3

TEXT

Description

Collagen has a triple-stranded rope-like coiled structure. The major collagen of skin, tendon, and bone is the same protein containing 2 alpha-1 polypeptide chains and 1 alpha-2 chain. Although these are long (the procollagen chain has a molecular mass of about 120 kD, before the 'registration peptide' is cleaved off; see 225410), each messenger RNA is monocistronic (Lazarides and Lukens, 1971). Differences in the collagens from these 3 tissues are a function of the degree of hydroxylation of proline and lysine residues, aldehyde formation for cross-linking, and glycosylation. The alpha-1 chain of the collagen of cartilage and that of the collagen of basement membrane are determined by different structural genes. The collagen of cartilage contains only 1 type of polypeptide chain, alpha-1, and this is determined by a distinct locus. The fetus contains collagen of distinctive structure. The genes for types I, II, and III collagens, the interstitial collagens, exhibit an unusual and characteristic structure of a large number of relatively small exons (54 and 108 bp) at evolutionarily conserved positions along the length of the triple-helical gly-X-Y portion (Boedtker et al., 1983). The family of collagen proteins consists of a minimum of 9 types of collagen molecules whose constituent chains are encoded by a minimum of 17 genes (Ninomiya and Olsen, 1984).


Cloning and Expression

Tromp et al. (1988) characterized a full-length cDNA clone for the COL1A1 gene.


Mapping

Sundar Raj et al. (1977) used the methods of cell hybridization and microcell hybridization to assign a collagen I gene to chromosome 17. Solomon and Sykes (1979) concluded, incorrectly as it turned out, that both the alpha-1 and the alpha-2 genes of collagen I are on chromosome 7. Solomon and Sykes (1979) also presented evidence that the alpha-1 chains of collagen III are also coded by chromosome 7. Church et al. (1981) assigned a structural gene for corneal type I procollagen to chromosome 7 by somatic cell hybridization involving corneal stromal fibroblasts. Because they had previously assigned a gene for skin type I procollagen to chromosome 17, they wondered whether skin and corneal type I collagen may be under separate control.

Huerre et al. (1982) used a cDNA probe in both mouse-man and Chinese hamster-man somatic cell hybrids to demonstrate cosegregation with human chromosome 17. In situ hybridization using the same probe indicated that the gene is in the middle third of the long arm, probably in band 17q21 or 17q22.

By chromosome-mediated gene transfer (CMGT), Klobutcher and Ruddle (1979) transferred the genes for thymidine kinase, galactokinase (604313), and type I procollagen (gene for alpha-1 polypeptide). The data indicated the following gene order: centromere--GALK--(TK1-COL1A1). Later studies (Ruddle, 1982) put the growth hormone gene cluster (see 139250) between GALK and (TK1-COL1A1).

A HindIII restriction site polymorphism in the alpha-1(I) gene was described by Driesel et al. (1982), who probably unjustifiably stated that the gene is on chromosome 7. By in situ hybridization, Retief et al. (1985) concluded that the alpha-1(I) and alpha-2(I) genes are located in bands 17q21.31-q22.05 and 7q21.3-q22.1, respectively.

Sippola-Thiele et al. (1986) commented on the limited number of informative RFLPs in the collagen genes, especially COL1A1. They proposed a method for assessing RFLPs that were otherwise undetectable in total human genomic DNA. Using the centromere-based locus D17Z1, Tsipouras et al. (1988) found a recombination fraction of 0.20 with COL1A1. Furthermore, they demonstrated that COL1A1 and GH1 (139250) show a recombination fraction of 0.10. They proposed that the most likely order is D17Z1--COL1A1--GH1.

Shupp Byrne and Church (1983) had concluded that both subunits of type I collagen, alpha-1 and alpha-2, are coded by chromosome 16 in the mouse. SOD1 (147450), which in man is on chromosome 21, is also carried by mouse 16. It may have been type VI collagen (120220, 120240) that they dealt with; both COL6A1 and COL6A2 are coded by human chromosome 21. (In fact, the Col6a1 and Col6a2 genes are carried by mouse chromosome 10 (Justice et al., 1990).) Munke et al. (1986) showed that the alpha-1 gene of type I collagen is located on mouse chromosome 11; the Moloney murine leukemia virus is stably integrated into this site when microinjected into the pronuclei of fertilized eggs. This insertion results in a lethal mutation through blockage of the developmentally regulated expression of the gene (Schnieke et al., 1983).


Molecular Genetics

Amino Acid Numbering System for COL1A1

Conventional numbering for the alpha-1(I) amino acid residues begins with the first glycine at the N-terminal end of the triple-helical domain. This numbering system is used in the list of allelic variants below.

Osteogenesis Imperfecta

Pope et al. (1985) described a substitution of cysteine in the C-terminal end of the alpha-1 collagen chain in a 9-year-old boy with mild osteogenesis imperfecta (OI) of Sillence type I (OI1; 166200). They assumed that this was a substitution for either arginine or serine (which could be accomplished by a single base change) because substitution of cysteine for glycine produced a much more drastic clinical picture. In a neonatal lethal case of OI congenita, or type II (OI2; 166210), Barsh and Byers (1981) demonstrated a defect in pro-alpha-1 chains

Byers et al. (1988) found an insertion in one COL1A1 allele in an infant with OI2. One alpha-1 chain was normal in length, whereas the other contained an insertion of approximately 50-70 amino acid residues within the triple-helical domain defined by amino acids 123-220. The structure of the insertion was consistent with duplication of an approximately 600-bp segment in 1 allele.

Brookes et al. (1989) used an S1 nuclease directed cleavage of heteroduplex DNA molecules formed between genomic material and cloned sequences to search for mutations in the COL1A1 gene in 5 cases in which previous linkage studies had shown the mutation to be located in the COL1A1 gene and in 4 cases in which a COL1A1 null allele had been identified by protein and RNA studies. No abnormality was found in the complete 18 kb COL1A1 gene or in 2 kb of 5-prime flanking sequence. The method used was known to permit the detection of short length variations of the order of 4 bp in heterozygous subjects but not single basepair alterations. Thus, Brookes et al. (1989) suggested that single basepair alterations may be the predominant category of mutation in type I OI.

COL1A1 and NGFR (162010) are in the same restriction fragment. In a 3-generation family with OI type I, Willing et al. (1990) found that all affected members had one normal COL1A1 allele and another from which the intragenic EcoRI restriction site near the 3-prime end of the gene was missing. They found, furthermore, a 5-bp deletion at the EcoRI site which changed the translational reading frame and predicted the synthesis of a pro-alpha-1(I) chain that extended 84 amino acids beyond the normal termination. Although the mutant chain was synthesized in an in vitro translation system, they were unable to detect its presence in intact cells, suggesting that it is unstable and rapidly destroyed in one of the cell's degradative pathways.

Cohn et al. (1990) demonstrated a clear instance of paternal germline mosaicism as the cause of 2 offspring with OI type I by different women. Both affected infants had a G-to-A change that resulted in substitution of aspartic acid for glycine at position 883 of the alpha-1 chain of type I collagen. Although not detected in the father's skin fibroblasts, the mutation was detected in somatic DNA from the father's hair root bulbs and lymphocytes. It was also found in the father's sperm where about 1 in 8 sperm carried the mutation, suggesting that at least 4 progenitor cells populate the germline in human males. The father was clinically normal. In an infant with perinatal lethal OI (OI type II), Wallis et al. (1990) demonstrated both normal and abnormal type I procollagen molecules. The abnormal molecules had substitution of arginine for glycine at position 550 of the triple-helical domain as a result of a G-to-A transition in the first base of the glycine codon. The father was shown to be mosaic for this mutation, which accounted for about 50% of the COL1A1 alleles in his fibroblasts, 27% of those in blood cells, and 37% of those in sperm. The father was short of stature; he had bluish sclerae, grayish discoloration of the teeth (which were small), short neck, barrel-shaped chest, right inguinal hernia, and hyperextensible fingers and toes. A triangular-shaped head had been noted at birth and he was thought to have hydrocephalus. No broken bones had been noted at that time. He had had only 1 fracture, that of the clavicle at age 8 years.

Cole et al. (1990) reported the clinical features of 3 neonates with lethal perinatal OI resulting from a substitution of glycine by arginine in the COL1A1 gene product. The mutations were gly391-to-arg, gly667-to-arg, and gly976-to-arg. All 3 were small, term babies who died soon after birth. The ribs were broad and continuously beaded in the first, discontinuously beaded in the second, and slender with few fractures in the third. The overall radiographic classifications were type IIA, IIA/IIB, and IIB, respectively (based on an old classification by Sillence et al., 1984; see HISTORY in 166210). The findings suggested that there was a gradient of bone modeling capacity from the slender and overmodeled bones associated with the mutation nearest the C-terminal end of the molecule to absence of modeling with that nearest the N-terminal end.

Dermal fibroblasts from most persons with OI type I produce about half the normal amount of type I procollagen as a result of decreased synthesis of one of its constituent chains, namely, the alpha-1 chain. Willing et al. (1992) used a polymorphic MnlI restriction endonuclease site in the 3-prime untranslated region of COL1A1 to distinguish the transcripts of the 2 alleles in 23 heterozygotes from 21 unrelated families with OI type I. In each case there was marked diminution in steady-state mRNA levels from one COL1A1 allele. They demonstrated that loss of an allele through deletion or rearrangement was not the cause of the diminished COL1A1 mRNA levels. Primer extension with nucleotide-specific chain termination allowed identification of the mutant allele in cell strains that were heterozygous for an expressed polymorphism. Willing et al. (1992) suggested that the method is applicable to sporadic cases, to small families, and to large families in which key persons are uninformative at the polymorphic sites used in linkage analysis.

Willing et al. (1993) pointed out that the abnormally low ratio of COL1A1 mRNA to COL1A2 (120160) mRNA in fibroblasts cultured from OI type I patients is an indication of a defect in the COL1A1 gene in the great majority of patients with this form of OI.

Byers (1993) counted a total of approximately 70 point mutations identified in the helical portion of the alpha-1 peptide, approximately 10 exon skipping mutations, and about 6 point mutations in the C-propeptide.

Steady state amounts of COL1A1 mRNA are reduced in both the nucleus and cytoplasm of dermal fibroblasts from most subjects with type I osteogenesis imperfecta (166200). Willing et al. (1995) investigated whether mutations involving key regulatory sequences in the COL1A1 promoter, such as the TATAAA and CCAAAT boxes, are responsible for the reduced levels of mRNA. They used PCR-amplified genomic DNA in conjunction with denaturing gradient gel electrophoresis and SSCP to screen the 5-prime untranslated domain, exon 1, and a small portion of intron 1 of the COL1A1 gene. In addition, direct sequence analysis was performed on an amplified genomic DNA fragment that included the TATAAA and CCAAAT boxes. In a survey of 40 unrelated probands with OI type I in whom no causative mutation was known, Willing et al. (1995) identified no mutations in the promoter region and there was 'little evidence of sequence diversity among any of the 40 subjects.'

Whereas most cases of severe osteogenesis imperfecta result from mutations in the coding region of the COL1A1 or COL1A2 genes yielding an abnormal collagen alpha-chain, many patients with mild OI show evidence of a null allele due to a premature stop mutation in the mutant RNA transcript. As indicated in 120150.0046, mild OI in one case resulted from a null allele arising from a splice donor mutation where the transcript containing the included intron was sequestered in the nucleus. Nuclear sequestration precluded its translation and thus rendered the allele null. Using RT-PCR and SSCP of COL1A1 mRNA from patients with mild OI, Redford-Badwal et al. (1996) identified 3 patients with distinct null-producing mutations identified from the mutant transcript within the nuclear compartment. In a fourth patient with a gly-to-arg expressed point mutation, they found the mutant transcript in both the nucleus and the cytoplasm.

Willing et al. (1996) analyzed the effects of nonsense and frameshift mutations on steady-state levels of COL1A1 mRNA. Total cellular and nuclear RNA was analyzed. They found that mutations which predict premature termination reduce steady-state amounts of COL1A1 mRNA from the mutant allele in both nuclear and cellular mRNA. The investigators concluded that premature termination mutations have a predictable and uniform effect on COL1A1 gene expression which ultimately leads to decreased production of type I collagen and to the mild phenotype associated with OI type I. Willing et al. (1996) reported that mutations which lead to premature translation termination appear to be the most common molecular cause of OI type I. They identified 21 mutations, 15 of which lead to premature termination as a result of translational frameshifts or single-nucleotide substitutions. Five mutations were splicing defects leading to cryptic splicing or intron retention within the mature mRNA. Both of these alternative splicing pathways indirectly lead to frameshifts and premature termination in downstream exons.

In 4 apparently unrelated patients with OI, Korkko et al. (1997) found 2 new recurrent nucleotide mutations in the COL1A1 gene, using a protocol whereby 43 exons and exon-flanking sequences were amplified by PCR and scanned for mutations by denaturing gradient gel electrophoresis. From an analysis of previous publications, they concluded that up to one-fifth of mutations causing OI are recurrent in the sense that they are identical in apparently unrelated probands. About 80% of these identical mutations were found to be in CpG dinucleotide sequences. Korkko et al. (1997) tabulated reported cases of recurrent mutations causing OI. The most frequent recurrent mutation was gly352ser (120150.0042), reported in 4 unrelated patients. They also reported a nonsense mutation in the codon for arginine-963 (120150.0055).

Since collagen I consists of 2 alpha-1 chains and 1 alpha-2 chain, a mutation in the COL1A1 gene might affect the function of the collagen molecule more than would a similar substitution in the COL1A2 gene, thereby causing more severe OI, for example. Lund et al. (1997) tested this hypothesis by comparing patients with identical substitutions in different alpha chains. They presented a G586V substitution in the alpha-1 gene (120150.0056) and compared it with a G586V substitution in the alpha-2 gene (120160.0023). Their patient had lethal OI type II. Patients with the same substitution in the alpha-2 chain had either OI type IV (OI4; 166220) or type III (OI3; 259420). Lund et al. (1997) pointed out that identical biochemical alterations in the same chain are known to have different phenotypic effects, both within families and between unrelated patients. They took this into account in their cautious proposal that substitutions in the alpha-1 chain may have more serious consequences than similar substitutions in the alpha-2 chain.

Kuivaniemi et al. (1997) summarized the data on 278 different mutations found in genes for types I, II, III, IX, X, and XI collagens from 317 apparently unrelated patients. Most mutations (217; 78% of the total) were single-base and either changed the codon of a critical amino acid (63%) or led to abnormal RNA splicing (13%). Most (155; 56%) of the amino acid substitutions were those of a bulkier amino acid replacing the obligatory glycine of the repeating Gly-X-Y sequence of the collagen triple helix. Altogether, 26 different mutations (9.4%) occurred in more than 1 unrelated individual. The 65 patients in whom the 26 mutations were characterized constituted almost one-fifth (20.5%) of the 317 patients analyzed. The mutations in these 6 collagens caused a wide spectrum of diseases of bone, cartilage, and blood vessels, including osteogenesis imperfecta, a variety of chondrodysplasias, types IV (130050) and VII (130060) Ehlers-Danlos syndrome, and, rarely, some forms of osteoporosis, osteoarthritis, and familiar aneurysms.

Dalgleish (1997) described a mutation database for the COL1A1 and COL1A2 genes.

Mutations in the COL1A2 gene appear to be very rare causes of type I osteogenesis imperfecta. Korkko et al. (1998) developed a method for analysis of the COL1A1 and COL1A2 genes in 15 patients with type I OI and found only COL1A1 mutations. They described their protocols for PCR amplification of the exon and exon boundaries of all 103 exons in the COL1A1 and COL1A2 genes. As previously pointed out, most mutations found in patients with OI type I introduce either premature termination codons or aberrant RNA splicing and thereby reduce the expression of the COL1A1 gene. The mutations tend to occur in common sequence context. All 9 mutations, found by Korkko et al. (1998) to convert the arginine codon CGA to the premature-termination codon TGA, occurred in the sequence context of G/CCC CGA GG/T of the COL1A1 gene. None was found in 7 CGA codons for arginine in other sequence contexts of the COL1A1 gene. The COL1A1 gene has 6 such sequences, whereas the COL1A2 gene has none.

Triple helix formation is a prerequisite for the passage of type I procollagen from the endoplasmic reticulum and secretion from the cell to form extracellular fibrils that will support mineral deposition in bone. In an analysis of cDNA from 11 unrelated individuals with osteogenesis imperfecta, Pace et al. (2001) found 11 novel, short in-frame deletions or duplications of 3, 9, or 18 nucleotides in the helical coding regions of the COL1A1 or COL1A2 collagen genes. Triple helix formation was impaired, type I collagen alpha chains were posttranslationally overmodified, and extracellular secretion was markedly reduced. With one exception, the obligate Gly-Xaa-Yaa repeat pattern of amino acids in the helical domains was not altered, but the Xaa and Yaa position residues were out of register relative to the amino acid sequences of adjacent chains in the triple helix. Thus, the identity of these amino acids, in addition to third position glycines, is important for normal helix formation. These findings expanded the repertoire of uncommon in-frame deletions and duplications in OI, and provided insight into normal collagen biosynthesis and collagen triple helix formation.

Cabral et al. (2001) reported a 13-year-old girl with severe type III OI in whom they identified heterozygosity for a gly76-to-glu substitution in the COL1A1 gene (120150.0065). The authors stated that this was the first delineation of a glutamic acid substitution in the alpha-1(I) chain causing nonlethal osteogenesis imperfecta.

Chamberlain et al. (2004) used adeno-associated virus vectors to disrupt dominant-negative mutant COL1A1 collagen genes in mesenchymal stem cells, also known as marrow stromal cells, from individuals with severe OI, demonstrating successful gene targeting in adult human stem cells.

Ehlers-Danlos Syndrome

In a girl with EDS VIIA (EDSARTH1; 130060) reported by Cole et al. (1986), Weil et al. (1989) identified a de novo heterozygous mutation in the COL1A1 gene that resulted in the skipping of exon 6 (120150.0026). The deleted peptides included those encoding the N-proteinase cleavage site necessary for proper collagen processing. D'Alessio et al. (1991) identified the same COL1A1 mutation in another child with EDS VIIA.

In a girl with EDSARTH1, Byers et al. (1997) identified a heterozygous splice site mutation in the COL1A1 gene, resulting in the skipping of exon 6 (120150.0057).

In a girl with severe EDSARTH1, Giunta et al. (2008) identified a heterozygous splice site mutation in the COL1A1 gene, resulting in the skipping of exon 6 (120150.0066).

In 2 unrelated patients with classic EDS (EDSCL1; 130000), Nuytinck et al. (2000) identified an arg134-to-cys mutation (120150.0059) in the COL1A1 gene.

Combined Osteogenesis Imperfecta and Ehlers-Danlos Syndrome 1

In 7 children with combined osteogenesis imperfecta and Ehlers-Danlos syndrome-1 (OIEDS1; 619115), Cabral et al. (2005) identified heterozygous mutations in the COL1A1 gene (see, e.g., 120150.0064). All of the mutations occurred in the first 90 residues of the helical region of alpha-1(I) collagen. These mutations prevented or delayed removal of the procollagen N-propeptide by purified N-proteinase (ADAMTS2; 604539) in vitro and in pericellular assays. The mutant pN-collagen which resulted was efficiently incorporated into matrix by cultured fibroblasts and osteoblasts and was prominently present in newly incorporated and immaturely cross-linked collagen. Dermal collagen fibrils had significantly reduced cross-sectional diameters, corroborating incorporation of pN-collagen into fibrils in vivo. The mutations disrupted a distinct folding region of high thermal stability in the first 90 residues at the amino end of type I collagen and altered the secondary structure of the adjacent N-proteinase cleavage site. Thus, these mutations are directly responsible for the bone fragility of OI and indirectly responsible for EDS symptoms, by interference with N-propeptide removal.

Cabral et al. (2005) hypothesized that the nature of EDS-like symptoms in OIEDS patients is similar to type VII EDS derived primarily by deletions of the N-propeptide cleavage site in alpha-1(I) and alpha-2(I) (120160) chains, in EDS VIIA (EDSARTH1; 130060) and VIIB (EDSARTH2; 617821), respectively, or by N-proteinase deficiency in EDS VIIC (EDSDRMS; 225410). It remained unclear why alpha-1(I)-OI/EDS patients had a somewhat different EDS phenotype (e.g., pronounced early scoliosis and no bilateral hip dysplasia) and why their collagen fibrils had more rounded cross-section under electron microscopy investigation. Makareeva et al. (2006) demonstrated that 85 N-terminal amino acids of the alpha1(I) chain participate in a highly stable folding domain, acting as the stabilizing anchor for the amino end of the type I collagen triple helix. This anchor region is bordered by a microunfolding region, 15 amino acids in each chain, which includes no proline or hydroxyproline residues and contains a chymotrypsin cleavage site. Glycine substitutions and amino acid deletions within the N-anchor domain induced its reversible unfolding above 34 degrees C. The overall triple helix denaturation temperature was reduced by 5 to 6 degrees C, similar to complete N-anchor removal. N-propeptide partially restored the stability of mutant procollagen but not sufficiently to prevent N-anchor unfolding and a conformational change at the N-propeptide cleavage site. The ensuing failure of N-proteinase to cleave at the misfolded site led to incorporation of pN-collagen into fibrils. As in EDS VIIA/B, fibrils containing pN-collagen are thinner and weaker causing EDS-like laxity of large and small joints and paraspinal ligaments. Makareeva et al. (2006) concluded that distinct structural consequences of N-anchor destabilization result in a distinct alpha1(I)-OI/EDS phenotype.

In 4 patients in a small pedigree with OIEDS, Cabral et al. (2007) identified heterozygosity for a c.3196C-T transition in the COL1A1 gene (120150.0071), resulting in an arg888-to-cys substitution in the Y position of one of the Gly-X-Y triplets that compose the collagen helix. The substitution in the Y position was shown to result in less delay in helix formation than would have been expected for a glycine substitution. Disulfide-bonded dimers of alpha(I) chains formed inefficiently in helices with 2 mutant chains; however, secretion from cells was normal. Formation of disulfide dimers at position 888 resulted in helix kinking, with resulting decreased helix stability and propagation of altered secondary structure along the remaining helix.

Malfait et al. (2013) sequenced the COL1A1 and COL1A2 genes in 7 patients with OIEDS1 or OIEDS2 (see 619120) and identified heterozygous mutations in the most N-terminal part of the type I collagen helix (2 in COL1A1 and 5 in COL1A2) in all patients. Both mutations in COL1A1 were missense (G188D; 120150.0072 and G203C) and the mutations in COL1A2 were 3 exon skipping and 2 missense. The mutations affected the rate of type I collagen N-propeptide cleavage and disturbed normal collagen fibrillogenesis.

By Sanger sequencing in a patient with OIEDS, Symoens et al. (2017) identified an in-frame 9-bp deletion in exon 44 of the COL1A1 gene (c.3150_3158del; 120150.0073), resulting in deletion of 3 amino acids in the collagen triple helix. The mutation was found to be present in mosaic state, which the authors concluded was responsible for the mild symptoms in the patient.

Caffey Disease

In affected individuals and obligate carriers from 3 unrelated families with Caffey disease (CAFYD; 114000), Gensure et al. (2005) identified heterozygosity for an arg836-to-cys mutation (R836C; 120150.0063) in the COL1A1 gene. Kamoun-Goldrat et al. (2008) identified heterozygosity for the R836C mutation in the COL1A1 gene in the pulmonary tissue of a fetus with a severe form of prenatal cortical hyperostosis (see 114000) from a terminated pregnancy at 30 weeks' gestation. The authors speculated that mutation in another gene might also be involved.

Susceptibility to Osteoporosis

Osteoporosis (166710) is a common disorder with a strong genetic component. One way in which the genetic component could be expressed is through polymorphism of COL1A1. Grant et al. (1996) described a novel G-to-T transversion at the first base of a binding site for the transcription factor Sp1 (189906) in intron 1 of COL1A1 (rs1800012; 120150.0051). They found that the polymorphism was associated with low bone density and increased appearance of osteoporotic vertebral fractures in 299 British women. In a study of 1,778 postmenopausal Dutch women, Uitterlinden et al. (1998) confirmed the association of the Sp1-binding site polymorphism and bone mineral density.

Lohmueller et al. (2003) performed a metaanalysis of 301 published genetic association studies covering 25 different reported associations. For 8 of the 25 associations, strong evidence of replication of the initial report was available. One of these 8 was the association between COL1A1 and osteoporotic fracture as first reported by Grant et al. (1996). Of a G/T SNP in intron 1, osteoporotic fractures showed association with the T allele.

In 1,873 Caucasian subjects from 405 nuclear families, Long et al. (2004) examined the relationship between 3 SNPs in the COL1A1 gene and bone size at the spine, hip, and wrist. They found suggestive evidence for an association with wrist size at SNP2 (p = 0.011): after adjusting for age, sex, height, and weight, subjects with the T allele of SNP2 had, on average, a 3.05% smaller wrist size than noncarriers. Long et al. (2004) concluded that the COL1A1 gene may have some effect on bone size variation at the wrist, but not at the spine or hip, in these families.

Jin et al. (2009) showed that the previously reported 5-prime untranslated region (UTR) SNPs in the COL1A1 gene (-1997G-T, rs1107946, 120150.0067; -1663indelT, rs2412298, 120150.0068; +1245G-T, rs1800012) affected COL1A1 transcription. Transcription was 2-fold higher with the osteoporosis-associated G-del-T haplotype compared with the common G-ins-G haplotype. The region surrounding rs2412298 recognized a complex of proteins essential for osteoblast differentiation and function including NMP4 (ZNF384; 609951) and Osterix (SP7; 606633), and the osteoporosis-associated -1663delT allele had increased binding affinity for this complex. Further studies showed that haplotype G-del-T had higher binding affinity for RNA polymerase II, consistent with increased transcription of the G-del-T allele, and there was a significant inverse association between carriage of G-del-T and bone mineral density (BMD) in a cohort of 3,270 Caucasian women. Jin et al. (2009) concluded that common polymorphic variants in the 5-prime UTR of COL1A1 regulate transcription by affecting DNA-protein interactions, and that increased levels of transcription correlated with reduced BMD values in vivo by altering the normal 2:1 ratio between alpha-1(I) and alpha-2(I) chains.


Genotype/Phenotype Correlations

Di Lullo et al. (2002) stated that binding sites on type I collagen had been elucidated for approximately half of the almost 50 molecules that had been found to interact with it. In addition, more than 300 mutations in type I collagen associated with human connective tissue disorders had been described. However, the spatial relationships between the ligand-binding sites and mutation positions had not been examined. Di Lullo et al. (2002) therefore created a map of type I collagen that included all of its ligand-binding sites and mutations. The map revealed several hotspots for ligand interactions on type I collagen and showed that most of the binding sites locate to its C-terminal half. Moreover, some potentially relevant relationships between binding sites were observed on the collagen fibril, including the following: fibronectin- and certain integrin-binding regions are near neighbors, which may mechanistically relate to fibronectin-dependent cell-collagen attachment; proteoglycan binding may influence collagen fibrillogenesis, cell-collagen attachment, and collagen glycation seen in diabetes and aging; and mutations associated with osteogenesis imperfecta and other disorders show apparently nonrandom distribution patterns within both the monomer and fibril, implying that mutation positions correlate with disease phenotype.

A missense mutation leading to the replacement of 1 Gly in the (Gly-Xaa-Yaa)n repeat of the collagen triple helix can cause a range of heritable connective tissue disorders that depend on the gene in which the mutation occurs. Persikov et al. (2004) found that the spectrum of amino acids replacing Gly was not significantly different from that expected for the COL7A1 (120120)-encoded collagen chains, suggesting that any Gly replacement will cause dystrophic epidermolysis bullosa (604129). On the other hand, the distribution of residues replacing Gly was significantly different from that expected for all other collagen chains studied, with a particularly strong bias seen for the collagen chains encoded by COL1A1 and COL3A1 (120180). The bias did not correlate with the degree of chemical dissimilarity between gly and the replacement residues, but in some cases a relationship was observed with the predicted extent of destabilization of the triple helix. Of the COL1A1-encoded chains, the most destabilizing residues (valine, glutamic acid, and aspartic acid) and the least destabilizing residue (alanine) were underrepresented. This bias supported the hypothesis that the level of triple-helix destabilization determines clinical outcome.

In an extensive review of published and unpublished sources, Marini et al. (2007) identified and assembled 832 independent mutations in the type I collagen genes (493 in COL1A1 and 339 in COL1A2). There were 682 substitutions of glycine residues within the triple-helical domains of the proteins (391 in COL1A1 and 291 in COL1A2) and 150 splice site mutations (102 in COL1A1 and 48 in COL1A2). One-third of the mutations that result in glycine substitutions in COL1A1 were lethal, whereas substitutions in the first 200 residues were nonlethal and had variable outcomes unrelated to folding or helix stability domains. Two exclusively lethal regions, helix positions 691-823 and 910-964, aligned with major ligand binding regions. Mutations in COL1A2 were predominantly nonlethal (80%), but lethal regions aligned with proteoglycan bindings sites. Splice site mutations accounted for 20% of helical mutations, were rarely lethal, and often led to a mild phenotype.

Rauch et al. (2010) compared the results of genotype analysis and clinical examination in 161 patients who were diagnosed as having OI type I, III, or IV according to the Sillence classification (median age: 13 years) and had glycine mutations in the triple-helical domain of alpha-1(I) (n = 67) or alpha-2(I) (n = 94). There were 111 distinct mutations, of which 38 affected the alpha-1(I) chain and 73 the alpha-2(I) chain. Serine substitutions were the most frequently encountered type of mutation in both chains. Overall, the majority of patients had a phenotypic diagnosis of OI type III or IV, had dentinogenesis imperfecta and blue sclera, and were born with skeletal deformities or fractures. Compared with patients with serine substitutions in alpha-2(I) (n = 40), patients with serine substitutions in alpha-1(I) (n = 42) on average were shorter (median height z-score -6.0 vs -3.4; P = 0.005), indicating that alpha-1(I) mutations cause a more severe phenotype. Height correlated with the location of the mutation in the alpha-2(I) chain but not in the alpha-1(I) chain. Patients with mutations affecting the first 120 amino acids at the N-terminal end of the collagen type I triple helix had blue sclera but did not have dentinogenesis imperfecta. Among patients from different families sharing the same mutation, about 90% and 75% were concordant for dentinogenesis imperfecta and blue sclera, respectively.

Takagi et al. (2011) reported 4 Japanese patients, including 2 unrelated patients with what the authors called 'classic OI IIC' and 2 sibs with features of 'OI IIC' but less distortion of the tubular bones (OI dense bone variant). No consanguinity was reported in their parents. In both sibs and 1 sporadic patient, they identified heterozygous mutations in the C-propeptide region of COL1A1 (120150.0069 and 120150.0070, respectively), whereas no mutation in this region was identified in the other sporadic patient. Familial gene analysis revealed somatic mosaicism of the mutation in the clinically unaffected father of the sibs, whereas their mother and healthy older sister did not have the mutation. Histologic examination in the 2 sporadic cases showed a network of broad, interconnected cartilaginous trabeculae with thin osseous seams in the metaphyseal spongiosa. Thick, cartilaginous trabeculae (cartilaginous cores) were also found in the diaphyseal spongiosa. Chondrocyte columnization appeared somewhat irregular. These changes differed from the narrow and short metaphyseal trabeculae found in other lethal or severe cases of OI. Takagi et al. (2011) concluded that heterozygous C-propeptide mutations in the COL1A1 gene may result in OI IIC with or without twisting of the long bones and that OI IIC appears to be inherited as an autosomal dominant trait.


Cytogenetics

COL1A1/PDGFB Fusion Gene

Dermatofibrosarcoma protuberans (DFSP; 607907), an infiltrative skin tumor of intermediate malignancy, presents specific cytogenetic features such as reciprocal translocations t(17;22)(q22;q13) and supernumerary ring chromosomes derived from t(17;22). Simon et al. (1997) characterized the breakpoints from translocations and rings in dermatofibrosarcoma protuberans and its juvenile form, giant cell fibroblastoma, on the genomic and RNA levels. They found that these rearrangements fuse the PDGFB gene (190040) and the COL1A1 gene. Simon et al. (1997) commented that PDGFB has transforming activity and is a potent mitogen for a number of cell types, but its role in oncogenic processes was not fully understood. They noted that neither COL1A1 nor PDGFB had hitherto been implicated in tumor translocations. The gene fusions deleted exon 1 of PDGFB and released this growth factor from its normal regulation; see 190040.0002.

Nakanishi et al. (2007) used RT-PCR to examine the COL1A1/PDGFB transcript using frozen biopsy specimens from 3 unrelated patients with DFSP and identified fusion of COL1A1 exon 25, exon 31, and exon 46, respectively, to exon 2 of the PDGFB gene. Clinical features and histopathology did not demonstrate any specific characteristics associated with the different transcripts.


Biochemical Features

Gauba and Hartgerink (2008) reported the design of a novel model system based upon collagen-like heterotrimers that can mimic the glycine mutations present in either the alpha-1 or alpha-2 chains of type I collagen. The design utilized an electrostatic recognition motif in 3 chains that can force the interaction of any 3 peptides, including AAA (all same), AAB (2 same and 1 different), or ABC (all different) triple helices. Therefore, the component peptides could be designed in such a way that glycine mutations were present in zero, 1, 2, or all 3 chains of the triple helix. They reported collagen mutants containing 1 or 2 glycine substitutions with structures relevant to native forms of OI. Gauba and Hartgerink (2008) demonstrated the difference in thermal stability and refolding half-life times between triple helices that vary only in the frequency of glycine mutations at a particular position.

By differential scanning calorimetry and circular dichroism, Makareeva et al. (2008) measured and mapped changes in the collagen melting temperature (delta-T(m)) for 41 different glycine substitutions from 47 OI patients. In contrast to peptides, they found no correlation of delta-T(m) with the identity of the substituting residue but instead observed regular variations in delta-T(m) with the substitution location on different triple helix regions. To relate the delta-T(m) map to peptide-based stability predictions, the authors extracted the activation energy of local helix unfolding from the reported peptide data and constructed the local helix unfolding map and tested it by measuring the hydrogen-deuterium exchange rate for glycine NH residues involved in interchain hydrogen bonds. Makareeva et al. (2008) delineated regional variations in the collagen triple helix stability. Two large, flexible regions deduced from the delta-T(m) map aligned with the regions important for collagen fibril assembly and ligand binding. One of these regions also aligned with a lethal region for Gly substitutions in the alpha-1(I) chain.


Animal Model

Pereira et al. (1993) established a line of transgenic mice that expressed moderate levels of an internally deleted human COL1A1 gene. The gene construct was modeled after a sporadic in-frame deletion that produced a lethal variant of OI. About 6% of the transgenic mice had a lethal phenotype with extensive fractures at birth, and 33% had fractures but were viable. The remaining 61% of the transgenic mice had no apparent fractures as assessed by x-ray examination on the day of birth. Brother-sister matings produced 8 litters in which approximately 40% of the mice had the lethal phenotype, indicating that expression of the transgene was more lethal in homozygous mice. The shortened collagen polypeptide chains synthesized from the human transgene were thought to bind to and produce degradation of the normal collagen genes synthesized from the normal mouse alleles. Khillan et al. (1994) extended these studies using an antisense gene. The strategy of specifically inhibiting expression of a gene with antisense RNA generated from an inverted gene was introduced in 1984 (Izant and Weintraub, 1984; Mizuno et al., 1984; and Pestka et al., 1984). Khillan et al. (1994) assembled an antisense gene that was similar to the internally deleted COL1A1 minigene used by Pereira et al. (1993) except that the 3-prime half of the gene was inverted so as to code for an antisense RNA. Transgenic mice expressing the antisense gene had a normal phenotype, apparently because the antisense gene contained human sequences instead of mouse sequences. Two lines of mice expressing the antisense gene were bred to 2 lines of transgenic mice expressing the minigene. In mice that inherited both genes, the incidence of the lethal fragile bone phenotype was reduced from 92 to 27%. The effect of the antisense gene was directly demonstrated by an increase in the ratio of normal mouse pro-alpha-1(I) chains to human mini-chains in tissues from mice that inherited both genes and had a normal phenotype. The results raised the possibility that chimeric gene constructs that contain intron sequences and in which only the first half of a gene is inverted may be particularly effective as antisense genes.

Pereira et al. (1994) used an inbred strain of transgenic mice expressing a mutated COL1A1 gene to demonstrate interesting features concerning phenotypic variability and incomplete penetrance. These phenomena are striking in families with osteogenesis imperfecta and are usually explained by differences in genetic background or in environmental factors. The inbred strain of transgenic mice expressing an internally deleted COL1A1 gene was bred to wildtype mice of the same strain so that the inheritance of proneness to fracture could be examined in a homogeneous genetic background. To minimize the effects of environmental factors, the phenotype was evaluated in embryos that were removed from the mother one day before term. Examination of stained skeletons from 51 transgenic embryos from 11 separate litters demonstrated that approximately 22% had a severe phenotype with extensive fractures of both long bones and ribs, approximately 51% had a mild phenotype with fractures of ribs only, and approximately 27% had no fractures. The ratio of steady-state levels of the mRNA from the transgene to the level of mRNA from the endogenous gene was the same in all transgenic embryos. The results demonstrated that the phenotypic variability and incomplete penetrance were not explained by variation in genetic background or levels in gene expression. Pereira et al. (1994) concluded from these results that phenotypic variation may be an inherent characteristic of the mutated collagen gene.

Pereira et al. (1998) studied a transgenic model of osteogenesis imperfecta (OI) in mice who expressed a mini-COL1A1 gene containing a large in-frame deletion. Marrow stromal cells from wildtype mice were infused into OI-transgenic mice. In mice that were irradiated with potentially lethal levels or sublethal levels, DNA from the donor marrow stromal cells was detected consistently in marrow, bone, cartilage, and lung at either 1 or 2.5 months after the infusion. The DNA also was detected, but less frequently, in the spleen, brain, and skin. There was a small but statistically significant increase in both collagen content and mineral content of bone 1 month after the infusion. In experiments in which male marrow stromal cells were infused into a female OI-transgenic mouse, fluorescence in situ hybridization assays for the Y chromosome indicated that after 2.5 months, donor male cells accounted for 4 to 19% of the fibroblasts or fibroblast-like cells obtained from primary cultures of the lung, calvaria, cartilage, long bone, tail, and skin. The results supported previous suggestions that marrow stromal cells or related cells in marrow serve as a source for continual renewal of cells in a number of nonhematopoietic tissues.

Aihara et al. (2003) evaluated intraocular pressure (IOP) in transgenic mice with a targeted mutation in the Col1a1 gene and found that the mice had ocular hypertension. The authors suggested an association between IOP regulation and fibrillar collagen turnover.

The mouse mutation 'abnormal gait-2' (Aga2) was identified in an N-ethyl-N- nitrosourea mutagenesis screen. Lisse et al. (2008) identified the Aga2 mutation as a T-to-A transversion within intron 50 of the Col1a1 gene, which introduced a novel 3-prime splice acceptor site that resulted in a frameshift. The mutant protein was predicted to have a novel C terminus that lacked a critical cysteine. Homozygosity for Aga2 was embryonic lethal. Heterozygous Aga2 (Aga2/+) animals showed early lethality, and surviving heterozygotes had widely variable phenotypes that included loss of bone mass, fractures, deformity, osteoporosis, and disorganized trabecular and collagen structures. Abnormal pro-Col1a1 chains accumulated intracellularly in Aga2/+ dermal fibroblasts and were poorly secreted. Intracellular accumulation of Col1a1 was associated with induction of an endoplasmic reticulum stress response and apoptosis characterized by caspase-12 (CASP12; 608633) and caspase-3 (CASP3; 600636) activation in vitro and in vivo.

Chen et al. (2014) reported a mouse model with a heterozygous T-C transition at a splice donor site of the Col1a1 gene, resulting in skipping of exon 9 and a predicted 18-amino acid deletion within the N-terminal region of the triple helical domain (Col1a1(Jrt)/+). Heterozygous mice are smaller than normal and have low bone mineral density and mechanically weak, fracture-prone bones, consistent with an osteogenesis imperfecta phenotype. The number of bone marrow stromal osteoprogenitors was normal, but mineralization was decreased in cultures from the heterozygous mice compared to wildtype mice. The heterozygous mice also had traits associated with Ehlers-Danlos syndrome, including reduced tensile properties of the skin, frayed tail tendon, and, in a third of the mice, noticeable curvature of the spine. The authors noted that this was the first reported animal model of the OI/EDS overlap syndrome.


ALLELIC VARIANTS 73 Selected Examples):

.0001   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY97ASP
SNP: rs72645333, ClinVar: RCV000018825

Byers (1990) provided information about this mutation in osteogenesis imperfecta type II (OI2; 166210).


.0002   OSTEOGENESIS IMPERFECTA, TYPE I

COL1A1, GLY94CYS
SNP: rs72645331, ClinVar: RCV000018826, RCV002247357

Starman et al. (1989) described a patient with OI type I (OI1; 166200) in whom a population of alpha-1(I) chains had a substitution of cysteine for glycine at position 94.


.0003   OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A1, GLY175CYS
SNP: rs66721653, ClinVar: RCV000018827, RCV002513110

In a patient with 'moderately severe' OI (OI4; 166220), de Vries and de Wet (1986, 1987) found a substitution of cysteine for glycine-175. Four persons in 3 generations were affected with striking variability in severity of fractures, deformity, and hearing loss, as well as presence or absence of blue sclerae and Wormian bones.


.0004   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY391ARG
SNP: rs72648363, ClinVar: RCV000018828

Bateman et al. (1987) characterized a structural defect of the alpha-1 chain of type I collagen in a baby with the lethal perinatal form of OI (OI2; 166210). The glycine residue at position 391 had been replaced by arginine. The substitution was associated with increased enzymatic hydroxylation of neighboring regions of the alpha-1 chain. This finding suggested that the sequence abnormality had interfered with the propagation of the triple helix across the mutant region. The abnormal collagen was not incorporated into the more insoluble fraction of bone collagen. The baby appeared to be heterozygous for the sequence abnormality, and, since the parents did not show any evidence of the defect, the authors concluded that the baby had a new mutation. The amino acid substitution could result from a single nucleotide change in the codon GGC (glycine) to produce the codon CGC (arginine).


.0005   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, GLY526CYS
SNP: rs67368147, ClinVar: RCV000018829, RCV000490665

In a patient with OI type III (OI3; 259420), Starman et al. (1989) identified a population of alpha-1(I) chains in which the glycine at position 526 was replaced by cysteine.


.0006   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY559ASP
SNP: rs72651651, gnomAD: rs72651651, ClinVar: RCV000018830

Byers (1990) characterized this mutation in a patient with OI type II (OI2; 166210).


.0007   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY673ASP
SNP: rs72653137, ClinVar: RCV000018831

Byers (1990) described this mutation in a patient with type II OI (OI2; 166210).


.0008   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY667ARG
SNP: rs72653136, ClinVar: RCV000018832, RCV000991594, RCV001236925

This mutation was originally thought to be a substitution of gly664-to-arg in the alpha-1(I) chain, but in fact alters residue 667 from glycine to arginine, according to Byers (1990). Bateman et al. (1988) originally described the mutation in osteogenesis imperfecta type II (OI2; 166210).


.0009   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY691CYS
SNP: rs72653143, ClinVar: RCV000018833, RCV002464069

Bateman et al. (1988) described this mutation in a patient with type II OI (OI2; 166210).


.0010   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY718CYS
SNP: rs72653152, ClinVar: RCV000018834

Starman et al. (1989) characterized this mutation in a patient with type II OI (OI2; 166210).


.0011   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY748CYS
SNP: rs72653154, ClinVar: RCV000018835

In a fetus with severe OI congenita (OI2; 166210), Vogel et al. (1987) found that a single nucleotide change, converting glycine 748 to cysteine in the alpha-1(I) chain, was responsible for destabilizing the triple helix and resulted in the lethal disorder. About 80% of the type I procollagen synthesized by the fibroblasts of the fetus had a decreased thermal stability. The fibroblasts of both parents were normal, indicating that this was a new mutation. Vogel et al. (1988) showed that the procollagen synthesized by the proband's cells is resistant to cleavage by procollagen N-proteinase, a confirmation-sensitive enzyme. Vogel et al. (1988) presented several space-filling models that might explain how the structure of the N-proteinase cleavage site could be affected by an amino acid substitution over 700 amino acid residues away.


.0012   OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A1, GLY832SER
SNP: rs72653169, ClinVar: RCV000018836

Marini et al. (1989) characterized this mutation in a patient with OI type IV (OI4; 166220). Also see Marini et al. (1993).


.0013   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, GLY844SER
SNP: rs66523073, ClinVar: RCV000018837, RCV003415717

Pack et al. (1989) described this mutation in a patient with OI type III (OI3; 259420). An unusual biochemical feature of this mutation was normal thermal stability of the intact type I collagen; multiple other mutations in which glycine is replaced result in significantly diminished thermal stability of the type I collagen molecule.


.0014   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY847ARG
SNP: rs72653172, ClinVar: RCV000018838

Wallis et al. (1990) described this mutation in OI type II (OI2; 166210).


.0015   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY883ASP
SNP: rs72654797, ClinVar: RCV000018839

Cohn et al. (1990) reported this mutation in a patient with OI type II (OI2; 166210). Recurrence of the OI type II phenotype in this family was explained by the finding of both somatic and germline mosaicism for this mutation in the father of the proband.


.0016   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY904CYS
SNP: rs72656303, ClinVar: RCV000018840

Constantinou et al. (1989) characterized this mutation in a patient with the perinatal lethal form of OI (OI2; 166210). The mutation caused the synthesis of type I procollagen that was posttranslationally overmodified, secreted at a decreased rate, and had a decreased thermal stability. Constantinou et al. (1990) demonstrated that the proband's mother had the same single base mutation as the proband. However, she had no fractures and no signs of OI except short stature, slightly blue sclerae, and mild frontal bossing; as a child, she had the triangular facies frequently seen in patients with OI. On repeated subculturing, the proband's fibroblasts grew more slowly than the mother's, but they continued to synthesize large amounts of the mutated procollagen in passages 7-14. In contrast, the mother's fibroblasts synthesized decreasing amounts of the mutated procollagen after passage 11. Also, the relative amount of the mutated allele in the mother's fibroblasts decreased with the passage number. In addition, the ratio of the mutated allele to the normal allele in leukocyte DNA from the mother was half the value in fibroblast DNA from the proband. Constantinou et al. (1990) concluded that the simplest interpretation of the findings was that the mother was mildly affected because she was mosaic for the mutation that produced a lethal phenotype in 1 of her 3 children. See also Cohn et al. (1990) and Wallis et al. (1990).


.0017   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY913SER
SNP: rs72656306, ClinVar: RCV000018841

Byers (1990) described this mutation in OI type II (OI2; 166210).


.0018   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY988CYS
SNP: rs72656324, ClinVar: RCV000018842

Steinmann et al. (1984) reported the protein abnormality in a cell line established from a patient with OI type II (OI2; 166210). Cohn et al. (1986) characterized the mutation.


.0019   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY1009SER
SNP: rs72656332, ClinVar: RCV000018843

Byers (1990) characterized this mutation in OI type II (OI2; 166210).


.0020   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, EX22DEL
ClinVar: RCV000018844

Wallis et al. (1989) described a mutation in COL1A1 resulting in the deletion of exon 22 during RNA processing. The phenotype was progressive deforming OI (OI3; 259420).


.0021   MOVED TO 120150.0022


.0022   OSTEOGENESIS IMPERFECTA

COL1A1, GLY1017CYS

Cohn et al. (1988) described a substitution of cysteine for glycine in the carboxy-terminal region of an alpha-1(I) chain in a patient with mild OI. Labhard et al. (1988) studied the same patient and identified the mutation as a heterozygous G-to-T transversion in the COL1A1 gene, resulting in a gly1017-to-cys (G1017C) substitution.

In a patient with 'moderately severe' OI, Steinmann et al. (1986) described an abnormal cysteine residue in cyanogen bromide peptide 6 of an alpha-1(I) chain. According to Byers (1990), the mutation causes substitution of cysteine for gly1017.


.0023   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, 9-BP DEL
ClinVar: RCV000018847

In a patient with the perinatal lethal form of OI (OI2; 166210), Wallis et al. (1989) described the heterozygous deletion of codons 874-876.


.0024   OSTEOGENESIS IMPERFECTA, TYPE I

COL1A1, FS
SNP: rs72656352, ClinVar: RCV000018848

Willing et al. (1990) reported a frameshift mutation near the 3-prime end of COL1A1 resulting in the phenotype of OI type I (OI1; 166200).


.0025   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, 1-BP INS, 4088T
ClinVar: RCV000018849

In a baby with the perinatal lethal form of OI (OI2; 166210), Bateman et al. (1989) identified heterozygosity for insertion of a single uridine nucleotide after basepair 4088 of the prepro-alpha-1(I) mRNA of type I collagen.

Cole et al. (1990) reported further on this patient whose x-ray changes were most consistent with OI IIB (based on an old classification by Sillence et al., 1984; see HISTORY in 166210).


.0026   EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 1

COL1A1, IVS6DS, G-A, -1
SNP: rs72667022, ClinVar: RCV000018852, RCV001851923

In a girl with Ehlers-Danlos syndrome type VIIA (EDSARTH1; 130060) reported by Cole et al. (1986), Weil et al. (1989) identified a de novo G-to-A transition in the last nucleotide of exon 6 of the COL1A1 gene, resulting in the skipping of exon 6 in the mRNA transcripts. The deleted peptides included those encoding the N-proteinase cleavage site necessary for proper collagen processing. The patient's unaffected parents did not carry the mutation. Further confirmation of the missplicing was obtained by transient expression. The child was born with bilateral dislocation of the hips and knees and mildly hyperelastic skin. At 4 years 7 months, her face had a chubby appearance due to laxity of facial tissues. Height was at the 3rd centile, which was thought to be due in part to progressive right thoracolumbar scoliosis. She also had a large inguinal hernia. Collagen fibrils in the skin were irregular in outline and varied widely in diameter. Cole et al. (1986) had identified a deletion of 24 amino acids (positions 136-159), corresponding to exon 6, from the pro-alpha-1(I) protein (Chu et al., 1984).

D'Alessio et al. (1991) identified the same heterozygous G-to-A mutation in another child with type VII EDS. The mutation resulted in a structural defect in the N terminus of the pro-alpha-1(I) collagen. The G-to-A transition was at the last nucleotide of exon 6 of the COL1A1 gene (which the authors stated corresponded to position -1 of the splice donor site of intron 6, IVS6DS, G-A, -1). The affected allele produced transcripts lacking exon 6 sequences and, in lesser amounts, normally spliced transcripts. The rate of exon 6 skipping was temperature dependent and appeared to decrease substantially when the patient's fibroblasts were incubated at 31 degrees C. The mutation was identical to that described by Weil et al. (1989). This mutation is identical to that found in COL1A2 (120160.0003).


.0027   MOVED TO 120150.0025


.0028   OSTEOGENESIS IMPERFECTA, TYPE I

COL1A1, GLY178CYS
SNP: rs72645365, ClinVar: RCV000018850

By chemical cleavage of DNA-DNA heteroduplexes, Valli et al. (1991) detected a single basepair mismatch in the COL1A1 gene in a patient with moderately severe osteogenesis imperfecta (OI1; 166200). The mismatch was found in about one-half of the heteroduplex molecules formed between the patient's mRNA and a normal cDNA probe. Sequencing demonstrated a single G-to-T substitution as the first base of the triplet coding for residue 178 of the triple-helical domain of the protein, leading to a glycine-to-cysteine substitution. Allele-specific oligonucleotide (ASO) hybridization to amplified DNA confirmed a de novo point mutation in the proband's genome.


.0029   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY541ASP
SNP: rs72651646, ClinVar: RCV000018851

See Zhuang et al. (1991).


.0030   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, GLY154ARG
SNP: rs72645357, ClinVar: RCV000018853, RCV000029586, RCV000480634, RCV000490676, RCV000692051, RCV000763413, RCV003398543

In 2 unrelated individuals with a progressive deforming variety of OI (OI3; 259420), Pruchno et al. (1991) found the same new dominant mutation, a substitution of arginine for glycine-154. The mutation occurred at a CpG dinucleotide in a manner consistent with deamination of a methylated cytosine residue. The findings indicated that the type III OI phenotype, previously thought to be inherited in an autosomal recessive manner, can result from new dominant mutations in the COL1A1 gene. Zhuang et al. (1996) found this mutation in a father and his 3 children.


.0031   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY1003SER
SNP: rs72656330, gnomAD: rs72656330, ClinVar: RCV000018854, RCV001811189

In 2 unrelated infants with perinatal lethal OI (OI2; 166210), Pruchno et al. (1991) observed a de novo dominant mutation that resulted in substitution of serine for glycine-1003. This mutation occurred at a CpG dinucleotide in a manner consistent with deamination of a methylated cytosine residue. Zhuang et al. (1996) found the same mutation in a father and his 3 children. The phenotypes of the patients included manifestations of types I and III/IV osteogenesis imperfecta, but appeared to be milder than the phenotype of the previously described 2 unrelated patients with the G415C mutation. Zhuang et al. (1996) speculated that other mutations in the type I collagen genes, environmental factors, mosaic status of the father, or genes at different loci might be responsible for the variable phenotype. They cited the evidence presented by Aitchison et al. (1988) and by Wallis et al. (1993) from linkage studies, indicating that genes other than the type 1 collagen genes may be involved in causing or modifying OI. The finding that allelic variants of the vitamin D receptor gene (277440) may correlate with low bone density provided another plausible explanation for a more severe phenotype in some individuals with OI due to identical mutations in the genes for type I collagen.


.0032   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY637VAL
SNP: rs66929517, ClinVar: RCV000018855

In a case of lethal osteogenesis imperfecta (OI2; 166210), Tsuneyoshi et al. (1991) demonstrated substitution of valine for glycine-637.


.0033   OSTEOGENESIS IMPERFECTA, TYPE III/IV

COL1A1, GLY415CYS
SNP: rs66527965, ClinVar: RCV000018856

In a male in his late 50s with osteogenesis imperfecta thought to be of either type III (OI3; 259420) or type IV (OI4; 166220), Nicholls et al. (1991) described heterozygosity for a substitution of cysteine for glycine at residue 415. Codon 415 was changed from GGC to TGC. The patient's first recorded fracture occurred at 6 weeks of age. Over the next 16 years he suffered more than 270 fractures leading to progressive skeletal deformity. His sclerae were reportedly bluish at birth but had become paler with age--a characteristic of type III OI. He had developed conductive hearing loss in his twenties, a feature not previously described in either type III or type IV. His teeth had been said to have been yellowish brown. The clinical phenotype and the position of the mutation conformed to the prediction of Starman et al. (1989) that the gly-to-cys mutations in the alpha-1(I) chain show a gradient of severity decreasing from the C-terminus to the N-terminus.


.0034   OSTEOGENESIS IMPERFECTA

COL1A1, GLY85ARG
SNP: rs72645323, ClinVar: RCV000018857

Deak et al. (1991) reported a 56-year-old male with mild osteogenesis imperfecta who underwent surgery for severe aortic valve regurgitation. He was of normal stature, with barrel chest and very pale blue sclera. Radiologic examination showed kyphoscoliosis and multiple compression fractures throughout the dorsal spine, although there was no history of spontaneous fractures. The aortic regurgitation was thought to be part of the connective tissue abnormality. Enlargement of the aortic root and mucinous degeneration of the aortic valve such as were found in this patient had been observed by Weisinger et al. (1975) and others. Deak et al. (1991) demonstrated substitution of arginine for glycine-85 in one of the 2 alpha-1(I) procollagen chains.


.0035   OSTEOGENESIS IMPERFECTA, TYPE IIC

COL1A1, GLY1006VAL
SNP: rs72656331, ClinVar: RCV000018858

In an infant with perinatal lethal osteogenesis imperfecta of the most severe clinical form, OI IIC (OI2; 166210), with premature rupture of membranes, severe antepartum hemorrhage, stillbirth, severe short-limbed dwarfism, and extreme osteoporosis, Cole et al. (1992) found a glycine-to-valine substitution at residue 1006 in the triple-helical domain of the alpha-1 chain of type I collagen.


.0036   OSTEOGENESIS IMPERFECTA, TYPE IIA

COL1A1, GLY973VAL
SNP: rs72656321, gnomAD: rs72656321, ClinVar: RCV000018859, RCV000657897

Cole et al. (1992) found substitution of valine for glycine at residue 973 in the triple-helical domain of the alpha-1 chain of type I collagen in an infant born prematurely as a result of premature rupture of membranes and severe antepartum hemorrhage. The infant had the radiographic features of OI IIA (166210).


.0037   OSTEOGENESIS IMPERFECTA, TYPE IIA

COL1A1, GLY256VAL
SNP: rs72648333, ClinVar: RCV000018860

In an infant with OI IIA (OA2; 166210), Cole et al. (1992) found substitution of valine for glycine at residue 256 in the triple-helical domain of the alpha-1 chain of type I collagen. Severe osteogenesis imperfecta can result from substitutions for glycine as far toward the amino-terminal as position 256. Cole et al. (1992) suggested that the type of glycine substitution which includes, in addition to valine, cysteine, arginine, aspartic acid, serine, alanine, tryptophan, and glutamic acid, and the site and surrounding sequences are probably important factors in determining the severity of the phenotype, i.e., whether it is OI I/IV, OI II, or OI III.


.0038   OSTEOGENESIS IMPERFECTA, TYPE I, MILD

COL1A1, GLY43CYS
SNP: rs72667037, ClinVar: RCV000018861, RCV001385346

Shapiro et al. (1992) described studies of a woman who at the age of 38, while still premenopausal, was found to have osteopenia, short stature, hypermobile joints, mild hyperelastic skin, mild scoliosis, and blue sclerae (see osteogenesis imperfecta type I, 166200). There was no history of vertebral or appendicular fracture. Hip and vertebral bone mineral density measurements were consistent with marked fracture risk. A basepair mismatch between the proband and control COL1A1 cDNA was detected by chemical cleavage with hydroxylamine:piperidine. Nucleotide sequence analysis demonstrated a G-to-T substitution in codon 43, replacing the expected glycine (GGT) residue with cysteine (TGT). Two of the woman's 4 children were similarly affected.


.0039   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, IVS14DS, G-A, +5
SNP: rs72645350, ClinVar: RCV000018862

In a fetus with type II OI (166210), Bonadio et al. (1990) demonstrated homozygosity for a G-to-A transition at the moderately conserved +5 position within the splice donor site of the COL1A1 gene. The mutation reduced the efficiency of normal splice site selection since the exon upstream of the mutation was spliced alternatively. The extent of alternative splicing was sensitive to the temperature at which the mutant cells were grown, suggesting that the mutation directly affected spliceosome assembly. The G-to-A transition appeared to be heterozygous at the level of mRNA and protein because it was unable to disrupt completely the normal exon 14 splicing. Bonadio et al. (1990) suggested that low level expression of alternative splicing (as could occur with heterozygous mutation) might be associated with mild dysfunction of connective tissue and perhaps, therefore, a phenotype different from osteogenesis imperfecta. The parents were unrelated and in their thirties at the time of the offspring's conception; neither parent had clinical signs or symptoms of OI. The diagnosis of short-limbed dwarfism was made on the fetus at 5 months of gestation and pregnancy was terminated electively. At autopsy, the fetus had all the characteristics of osteogenesis imperfecta congenita. DNA studies in both parents showed absence of the mutation in all cells studied (Bonadio, 1990). Bonadio (1990) found evidence suggesting uniparental disomy for chromosome 17. A new mutation in 1 parent combined with uniparental disomy would explain the functional homozygosity of the mutation in the fetus. Bonadio (1992) had not had an opportunity to study the possibility further.


.0040   OSTEOGENESIS IMPERFECTA, TYPE I

COL1A1, GLY901SER
SNP: rs72654802, ClinVar: RCV000018863, RCV001596935, RCV003398544

Mottes et al. (1992) identified a GGC (gly) to AGC (ser) transition in codon 901 of the COL1A1 gene in an 8-year-old boy with repeated fractures of both femora. Intramedullar rodding had been performed at the age of 3 years. His mother, 44 years old at the time of his birth, was short (140 cm) and had mild hypoacusis from age 40 and moderate osteoporosis but had never had fractures. The mother was likewise heterozygous for the gly901-to-ser mutation. The mild phenotype was surprising in light of the usual experience that glycine substitutions in the C-terminal region of the collagen triple helix cause lethal OI. The patient was classified as OI type IB on the basis of the absence of dentinogenesis imperfecta (see 166200).


.0041   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY802VAL
SNP: rs72653166, ClinVar: RCV000018864, RCV003228896

In the surviving child in a family in which the 2 sibs had clinical and radiologic features typical of lethal OI (166210) (Cohen-Solal et al., 1991), Bonaventure et al. (1992) used chemical cleavage of cDNA-RNA heteroduplexes to identify a mismatch in COL1A1 cDNA. The mismatch was subsequently confirmed by sequencing a PCR-amplified fragment and was demonstrated to be due to a G-to-T transversion in the second base of the first codon of exon 41 resulting in the substitution of glycine-802 by valine. The mutation impaired collagen secretion by dermal fibroblasts. The overmodified chains were retained intracellularly. The mutant allele was demonstrated in the mother's leukocytes but not in her fibroblasts, and collagen synthesized by the fibroblasts of both parents was normal. The findings suggested the presence of somatic and germline mosaicism in the phenotypically normal mother, explaining the recurrence of OI.


.0042   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, GLY352SER
SNP: rs67682641, ClinVar: RCV000018865, RCV000548768, RCV003327362

In a 6.5-year-old girl with 'moderately severe OI' (259420), Marini et al. (1993) observed substitution of serine for glycine-352 in the alpha-1 chain of type I collagen. This substitution was produced by a G-to-A transition in 1 allele.


.0043   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, EX15-16DUP
SNP: rs2144577336, ClinVar: RCV000018866

In an infant with the lethal form of osteogenesis imperfecta (166210), Cohn et al. (1993) characterized a tandem duplication mutation within the COL1A1 gene. The structure of the mutation was consistent with unequal crossing over within a 15-bp region of sequence identity between exons 14 and 17. The recombination produced a new 81-bp 17/14 hybrid exon and complete duplication of exons 15 and 16. The sequence implied duplication of 60 amino acid residues within the triple-helical domain with preservation of the Gly-X-Y repeat. The process was thought to mimic that by which the triple-helical domain of fibrillar collagen genes arose in evolution by repeated tandem duplication of an ancestral unit exon.


.0044   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY415SER
SNP: rs66527965, ClinVar: RCV000018867, RCV000626590, RCV001596936, RCV001813997

In a female infant who died in her first hour of life because of respiratory failure and showed the features of severe osteogenesis imperfecta thought to fall between type II (166210) and type III (259420) of Sillence, Mottes et al. (1993) demonstrated by chemical cleavage of mismatched bases and subsequent sequencing a G-to-A transition that caused substitution of gly415 with serine. The same mutation was found in the clinically normal father's spermatozoa and lymphocytes. Mosaicism in the father's germline explained the occurrence in the family of 2 later pregnancies in which OI was documented by radiographs and ultrasound investigations.


.0045   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY565VAL
SNP: rs72651653, ClinVar: RCV000018868

In an infant with osteogenesis imperfecta type IIA (166210) born of a 37-year-old mother and a 39-year-old father, Mackay et al. (1993) mapped the defect in type I collagen to alpha-1 cyanogen bromide peptide 7, a region corresponding to 271 amino acid residues of either the alpha-1 or the alpha-2 chain of type I collagen. Polymerase chain reaction amplification of the corresponding region of the alpha-1(I) mRNA followed by SSCP analysis of restriction enzyme digests of the PCR products allowed further mapping of the mutation to a small region of the COL1A1 gene. A heterozygous G-to-T transversion within the last splicing codon of exon 32 was identified by DNA sequence analysis. This mutation had resulted in the substitution of glycine-565 by a valine residue. The mutation was shown to have occurred de novo.


.0046   OSTEOGENESIS IMPERFECTA, TYPE I

COL1A1, IVS26DS, G-A, +1
SNP: rs66555264, ClinVar: RCV000490727, RCV000599354, RCV000763410, RCV002221545, RCV003403127

Stover et al. (1993) demonstrated defective splicing of mRNA from one COL1A1 allele in a patient with mild type I OI (166200). Genovese et al. (1989) had demonstrated that dermal fibroblasts from this patient showed a novel species of COL1A1 mRNA in the nuclear compartment of cells; that it was not collinear with a cDNA probe, and, therefore, with the fully spliced COL1A1 mRNA, was indicated by indirect RNase protection assays. Stover et al. (1993) showed that a G-to-A transition in the first position of the donor site of intron 26 resulted in the inclusion of the entire sequence in the mature mRNA that accumulated in the nuclear compartment. The retained intron contained an in-frame stop codon and introduced an out-of-frame insertion within the collagen mRNA producing stop codons downstream of the insertion. These changes probably accounted for the failure of the mutant RNA to appear in the cytoplasm. Unlike other splice site mutations within collagen mRNA that resulted in exon skipping and a truncated but in-frame RNA transcript, this mutation did not result in production of a defective COL1A1 chain. Instead, the mild nature of the disease in this patient reflected failure to process a defective mRNA and, thus, the absence of a protein product from the mutant allele.


.0047   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY355ASP
SNP: rs72648356, ClinVar: RCV000018870

Raghunath et al. (1994) developed a method for early prenatal diagnosis of molecular disorders involving types I and III collagens. The method took advantage of the fact that isolated chorionic villi contain significant amounts of collagen in their extracellular matrix and synthesize collagens in vitro. They correctly predicted a healthy fetus and an embryo affected with lethal osteogenesis imperfecta (166210) in consecutive pregnancies from a couple in which the asymptomatic mother was a somatic mosaic for a COL1A1 G-to-A transition resulting in substitution of glycine-355 by aspartic acid. Steinmann (1994) stated that this is the sixth gly-to-asp substitution in the alpha-1(I) chain, all of which have been associated with lethal OI regardless of position of the mutation. This was, furthermore, the ninth example of molecularly proven mosaicism. The asymptomatic mother was 153 cm tall and was shorter by 12 to 22 cm than her female first-degree relatives.


.0048   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, GLY862SER
SNP: rs72653178, ClinVar: RCV000018871, RCV000518360, RCV001245193

Namikawa et al. (1995) identified a heterozygous gly862-to-ser substitution in 2 sibs with type III osteogenesis imperfecta (259420). The mutation was also detected in various paternal tissues; the mutant allele accounted for approximately 11% of the COL1A1 alleles in blood, 24% of those in fibroblasts, and 43% of those in sperm. The father was phenotypically normal. The parents were nonconsanguineous. The first-born child died of respiratory failure at age 3 years after repeated hospital admissions for recurrent fractures and respiratory insufficiency. The second-born child was identified as having OI by ultrasonography at 32 weeks' gestation on the basis of angulated femoral bones. The father had no history of fractures or other indications of connective tissue disease. His height was 173 cm (73th percentile for a 30- to 39-year-old Japanese male) and he was taller than his father. His weight was at the 62nd percentile. Skin, joints, sclera, and teeth were normal. Germline mosaicism was obviously responsible for the recurrence. Namikawa et al. (1995) pointed out that there is a cluster of gly-to-ser substitutions associated with nonlethal phenotypes (gly832-to-ser, gly844-to-ser, and gly901-to-ser (120150.0040), with gly862-to-ser in the middle) and that this nonlethal cluster is located between 2 lethal clusters.


.0049   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, GLY661SER
SNP: rs72653131, ClinVar: RCV000018872, RCV000490682

Nuytinck et al. (1996) observed this mutation in a severely affected infant with type III OI (259420). The same mutation in the COL1A2 gene (120160.0030) results in a much milder phenotype, namely post menopausal osteoporosis.


.0050   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, LEU-PRO, C-TER PROPEPTIDE
SNP: rs72656353, ClinVar: RCV000018873, RCV003517128

Oliver et al. (1996) described unusual molecular findings in a young girl who presented with severe type III OI (259420). Her otherwise healthy mother had pale blue sclerae and recurrent joint dislocations of the ankles, shoulders, knees, elbows, wrists, and neck from 8 years of age. She suffered dislocation of the left hip during the pregnancy. The maternal grandfather was 177 cm tall and had recurrent dislocations of the right elbow and right knee since age 10 years. He had pale blue sclerae from childhood. He developed progressive deafness of the left ear, and later Meniere disease. The proposita had dark blue sclerae and multiple old and new fractures at birth. Subsequently she suffered at least 200 fractures, mostly of the femurs. At 3 years of age the sclerae were pale blue. There was a severe pectus carinatum. The skin was abnormally soft, and there was marked generalized joint laxity. The broad forehead and triangular shaped face were typical of OI. Teeth and hearing were normal and she did not bruise easily. Skin fibroblast cultures from the child produced both normal and posttranslationally overmodified type I collagen. Cyanogen bromide peptide maps of the abnormal protein indicated a C-terminal mutation. Examination of the C-propeptide sequences demonstrated 2 heterozygous single base changes in the child. One, an A-to-C transversion changing threonine to proline at residue 29 of the COL1A2 C-propeptide, was also present in the mother and maternal grandfather but not in 50 unrelated controls. The second mutation, a T-to-C transition, altered the last amino acid residue of the COL1A1 C-propeptide from leucine to proline and had occurred de novo in the affected child. The latter mutation was thought to be responsible for OI. Oliver et al. (1996) stated that the most frequent cause of excess posttranslational modification of collagens is the substitution of glycine in 1 Gly-X-Y repeat unit of the triple helix. No such mutation was detected in the proband. They commented that the change in the COL1A2 gene may have been related to the connective tissue manifestations in the mother and maternal grandfather.


.0051   BONE MINERAL DENSITY VARIATION QUANTITATIVE TRAIT LOCUS

COL1A1, IVS1, 2046G-T ({dbSNP rs1800012})
SNP: rs1800012, gnomAD: rs1800012, ClinVar: RCV000018874

Screening the COL1A1 transcriptional control regions by PCR-SSCP in a sample of 50 subjects, Grant et al. (1996) found 3 polymorphisms in the first intron, 2 of which were rare (allele frequency approximately 4% and 3%) and 1 common (allele frequency approximately 22%). The common polymorphism was characterized as a G-to-T substitution at the first base of a consensus site for the transcription factor Sp1 (189906) in the first intron of COL1A1 (nucleotide 2046). Grant et al. (1996) devised a PCR-based screen and studied allele distribution in 2 populations of British women, 1 in Aberdeen and 1 in London. They found that the G/T polymorphism was significantly related to bone mass and osteoporotic fracture (166710). G/T heterozygotes had significantly lower bone mineral density (BMD) than G/G homozygotes (SS) in both populations, and BMD was lower still in G/T homozygotes (ss). The unfavorable Ss and ss genotypes were over-represented in patients with severe osteoporosis and vertebral fractures (54%), as compared with controls (27%) equivalent to a relative risk of 2.97 for vertebral fracture in individuals who carried the 's' allele. These results were confirmed and extended by Uitterlinden et al. (1998).

Uitterlinden et al. (1998) studied the Sp1-binding site polymorphism in 1,778 postmenopausal women in the Netherlands and found that compared with the 1,194 women with the SS genotype, the 526 women with the Ss genotype had 2% lower bone mineral density at the femoral neck (p = 0.003) and the lumbar spine (p = 0.02); the 58 women with the ss genotype had reductions of 4% at the femoral neck (p = 0.05) and 6% at the lumbar spine (p = 0.005). These differences increased with age. Women with the Ss and ss genotypes were overrepresented among the 111 women who had incident nonvertebral fractures.

Uitterlinden et al. (2001) studied the interaction between polymorphisms of the vitamin D receptor gene (VDR; 601769) and the Sp1-binding site polymorphism of COL1A1 and concluded that interlocus interaction is likely to be an important component of osteoporotic fracture risk.

Sainz et al. (1999) studied the Sp1-binding site polymorphism and measurements of the size and the density of vertebral bone in 109 healthy prepubertal girls. On average, 22 girls with the Ss genotype and 1 girl with the ss genotype had 6.7% and 33.2% lower cancellous bone density in the vertebrae, respectively, than girls with the SS genotype. In contrast, there was no association between the size of the vertebrae and the COL1A1 genotypes. (One of the authors (Gilsanz, 2008) noted that the correct ss genotype figure is 33.2% rather than the 49.4% cited in the 1999 article.)

In an association study involving 3,270 women enrolled in an osteoporosis screening program, Stewart et al. (2006) analyzed 3 SNPs in the promoter and intron 1 of the COL1A1 gene (the Sp1-binding site polymorphism rs1800012, which they designated +1245G/T; rs1107946, and rs2412298) and their haplotypes. The polymorphisms were in strong linkage disequilibrium and 3 haplotypes accounted for more than 95% of the alleles at the COL1A1 locus. Homozygote carriers of 'haplotype 2' had reduced BMD, whereas homozygote carriers of 'haplotype 3' had increased BMD. Stewart et al. (2006) concluded that there is bidirectional regulation of BMD by the 2 haplotypes in the 5-prime flank of COL1A1.

In a case-control study of 206 Caucasians with otosclerosis (see 166800) and 282 Caucasian controls, Chen et al. (2007) identified 2 haplotypes, composed of 5 SNPs in the COL1A1 gene (rs1800012, rs9898186, rs2269336, rs11327935, and rs1107946), that were significantly associated with otosclerosis. In osteoblast cell lines, the protective H2 haplotype decreased promoter activity, whereas the susceptibility H3 haplotype increased promoter activity by affecting binding of transcription factors to cis-acting elements, suggesting that increased amounts of collagen alpha-1 homotrimers are causally related to the development of otosclerosis. Consistent with this hypothesis, Chen et al. (2007) demonstrated hearing loss in mice from a naturally occurring mutant strain that only deposits homotrimeric type I collagen. The authors designated the Sp1-binding site polymorphism, rs1800012, as +1126G/T.

Jin et al. (2009) showed that the previously reported 5-prime untranslated region (UTR) SNPs in the COL1A1 gene (-1997G-T, rs1107946, 120150.0067; -1663indelT, rs2412298, 120150.0068; +1245G-T, rs1800012) affected COL1A1 transcription. Transcription was 2-fold higher with the osteoporosis-associated G-del-T haplotype compared with the common G-ins-G haplotype. The region surrounding rs2412298 recognized a complex of proteins essential for osteoblast differentiation and function including NMP4 (ZNF384; 609951) and Osterix (SP7; 606633), and the osteoporosis-associated -1663delT allele had increased binding affinity for this complex. Further studies showed that haplotype G-del-T had higher binding affinity for RNA polymerase II, consistent with increased transcription of the G-del-T allele, and there was a significant inverse association between carriage of G-del-T and bone mineral density (BMD) in a cohort of 3,270 Caucasian women. Jin et al. (2009) concluded that common polymorphic variants in the 5-prime UTR of COL1A1 regulate transcription by affecting DNA-protein interactions, and that increased levels of transcription correlated with reduced BMD values in vivo by altering the normal 2:1 ratio between alpha-1(I) and alpha-2(I) chains.


.0052   OSTEOGENESIS IMPERFECTA, TYPE I, MILD

COL1A1, GLY13ALA
SNP: rs67828806, ClinVar: RCV000018875, RCV001242940

Mayer et al. (1996) described a G-to-C transversion in 1 COL1A1 allele resulting in a gly13-to-ala substitution in the triple-helical domain of the pro-alpha-1(I) collagen chain. The mutation was found in a 35-year-old woman with a mild form of osteogenesis imperfecta type I (166200) who presented with spontaneous dissection of the right internal carotid artery and the right vertebral artery after scuba diving but without obvious head or neck trauma. Other than a history of easy bruising and bluish sclerae, she had no evidence of a connective tissue disorder. There had been no bone fractures or dental problems nor was there family history of vasculopathy.


.0053   OSTEOGENESIS IMPERFECTA, TYPE II, THIN-BONE TYPE

COL1A1, TRP94CYS
SNP: rs72656343, ClinVar: RCV000018876

Cole et al. (1996) described an infant with lethal perinatal osteogenesis imperfecta (166210) resulting from the substitution of trp94 by cysteine (Y94C) in the C-terminal propeptide of the pro-alpha-1(I) chain. The infant was born at 38 weeks' gestation with numerous fractures of the limbs, skull, and ribs, and with subarachnoid and subdural hemorrhages. Death from respiratory distress occurred within hours of birth. The limbs and torso were of normal length, shape, and proportion. All bones were relatively normal in shape and the long bones showed normal metaphyseal modeling. These clinical and radiographic features were similar to those observed in another baby with OI II resulting from a mutation of the C-terminal propeptide of the pro-alpha-1 chains (Bateman et al., 1989; Cole et al., 1990), but dissimilar from those reported in babies with OI II resulting from helical mutations of type 1 collagen. Cole et al. (1996) stated that the infant's Y94C mutation disturbed procollagen folding and retarded the formation of disulfide-linked trimers. The endoplasmic reticulum resident molecular chaperone BiP, which binds to malfolded proteins, was induced and bound to type I procollagen produced by the OI fibroblasts. Unassembled mutant pro-alpha-1 chains were also retained in the rough endoplasmic reticulum.


.0054   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, 562-BP DEL
SNP: rs1906960583, ClinVar: RCV000018877

Wang et al. (1996) identified a novel multiexon deletion in a COL1A1 allele. They examined a 9-year-old girl and her 37-year-old father, both affected with severe OI type III (259420). SSCP and PCR were used to identify a 562-bp deletion extending from the last 3 nucleotides of exon 34 to 156 nucleotides from the 3-prime end of intron 36. This deletion was also detected in the clinically normal grandmother, who was confirmed to be a mosaic carrier. Three alternative forms of mutant mRNA resulted from this deletion. One form had a deletion with end points identical to the genomic deletion, resulting in an in-frame mutant mRNA. The second in-frame form used the normal exon 32 splice donor and the exon 37 acceptor. The out-of-frame third form used a cryptic donor site in exon 34 and the exon 37 acceptor site. Although the in-frame forms of mRNA constituted 60% of the mRNA, no mutant protein was detected in cultured fibroblasts or in cultured osteoblasts of the patients.

Cabral and Marini (2004) examined a mosaic carrier in the family previously reported by Wang et al. (1996), the mother of the 'father.' She was 67 years old when she died of pneumonia after an intracranial hemorrhage. Two of her 7 children had severe OI type III. One affected son died of pneumonia as a child. On physical examination, the mosaic carrier had normal height (161 cm; 50th percentile for adult women) and well-proportioned span. The only manifestations of a connective tissue disorder were blue sclerae and a triangular-shaped facies. She had never sustained a fracture. Bone histology was normal. Thus, in OI, substantially normal skeletal growth, density, and histology are compatible with a 40 to 75% burden of osteoblasts heterozygous for a COL1A1 mutation. These data were considered encouraging for mesenchymal stem cell transplantation, since mosaic carriers are a naturally occurring model for cell therapy.


.0055   OSTEOGENESIS IMPERFECTA, TYPE I

COL1A1, ARG963TER
SNP: rs72656314, gnomAD: rs72656314, ClinVar: RCV000018878, RCV000582506, RCV000599479

Korkko et al. (1997) found that 2 unrelated patients with type I osteogenesis imperfecta (166200) had identical mutations that converted the codon for arginine-963 from CGA to TGA (stop). Willing et al. (1994) also reported this nucleotide change in a patient with type 1 OI.


.0056   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, GLY586VAL
SNP: rs72651657, ClinVar: RCV000018879

Forlino et al. (1994) described type III OI in a patient with a G586V substitution in the alpha-2 chain of collagen I (120160.0023). Lund et al. (1997) described the same mutation, a G586V substitution, in the alpha-1 chain in a case of lethal OI type II (166210). They presented this as evidence that, perhaps because there are 2 alpha-1 chains and 1 alpha-2 chain in type I collagen, substitutions in the alpha-1 gene have more serious consequences. They pointed out that identical biochemical alterations in the same chain are known to have different phenotypic effects, both within families and between unrelated patients.


.0057   EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 1

COL1A1, IVS5AS, G-A, -1
SNP: rs72667020, gnomAD: rs72667020, ClinVar: RCV000018880

In a girl with arthrochalasia-type Ehlers-Danlos syndrome (EDSARTH1; 130060), born of a 23-year-old Caucasian father and a 31-year-old mother of Japanese origin, Byers et al. (1997) identified a heterozygous G-to-A transition at position -1 of the splice acceptor site of intron 5 of the COL1A1 gene, resulting in the skipping of exon 6. She presented at birth with large fontanels, a small umbilical hernia, joint laxity, contractures of the digits of both hands, short femurs, pendulous skin folds, and bilateral hip dislocation. PCR amplification around exon 6 of the alpha-1 cDNA produced 3 bands, one of a normal size, a second about 15 to 20 bp smaller, and a third equivalent to the product expected with deletion of the sequence of the entire exon 6. The sequence of the smaller band indicated that there was a deletion of 15 bp encoding 5 amino acids (asn-phe-ala-pro-gln), which included the pepsin-sensitive site (phe-ala) and the N-proteinase cleavage site (pro-gln).


.0058   OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A1, IVS8DS, G-A, +1
SNP: rs67364703, ClinVar: RCV000018882

Schwarze et al. (1999) reported a patient thought to have moderately severe osteogenesis imperfecta type IV (166220). Between ages 10 months and 9 years, she sustained several dozen spontaneous fractures to the bones of her legs, hands, and feet. After age 9 years, the fracture frequency decreased dramatically. At this point, she was growth retarded, with a height of 112 cm, which corresponded to her adult height. Her virtual cessation of growth was attributed, in part, to progressive scoliosis and moderate deformity of her lower limbs. Her mobility was reduced, and she spent most of her time in a wheelchair. Her sclerae remained grayish-blue. In this patient, Schwarze et al. (1999) identified a G-to-A transition at the +1 position of intron 8 of the COL1A1 gene. They stated that most splice site mutations lead to a limited array of products, including exon skipping, use of cryptic splice acceptor or donor sites, and intron inclusion. In the patient reported by Schwarze et al. (1999), however, the splice site mutation resulted in the production of several splice products from the mutant allele. These included 1 in which the upstream exon 7 was extended by 96 nucleotides, others in which either intron 8 or introns 7 and 8 were retained, 1 in which exon 8 was skipped, and 1 that used a cryptic donor site in exon 8. To determine the mechanism by which exon 7 redefinition might occur, Schwarze et al. (1999) examined the order of intron removal in the region of the mutation by using intron/exon primer pairs to amplify regions of the precursor nuclear mRNA between exon 5 and exon 10. Removal of introns 5, 6, and 9 was rapid. Removal of intron 8 usually preceded removal of intron 7 in the normal gene, although, in a small proportion of copies, the order was reversed. The proportion of abnormal products suggested that exon 7 redefinition, intron 7 plus intron 8 inclusion, and exon 8 skipping all represented products of the impaired rapid pathway, whereas the intron 8 inclusion product resulted from use of the slow intron 7-first pathway. The very low-abundance cryptic exon 8 donor site product could have arisen from either pathway. Schwarze et al. (1999) interpreted the results as suggesting that there is commitment of the pre-mRNA to the 2 pathways, independent of the presence of the mutation, and that the order and rate of intron removal are important determinants of the outcome of splice site mutations and may explain some unusual alterations.


.0059   EHLERS-DANLOS SYNDROME, CLASSIC TYPE

COL1A1, ARG134CYS
SNP: rs72645347, ClinVar: RCV000018884, RCV000415259, RCV000631472, RCV001198512, RCV002276563, RCV002496407, RCV003225023

In 2 unrelated patients with classic Ehlers-Danlos syndrome (see 130000), Nuytinck et al. (2000) found the same mutation in the COL1A1 gene. The first patient was a 5-year-old girl who had been born near term, after premature rupture of membranes. She had a history of easy bruising and scarring after minimal trauma and presented soft velvety, and hyperextensible skin. In addition, she had atrophic paper scars on the face, elbows, knees, and shins; ecchymoses on the lower legs; and generalized joint hyperlaxity. Her facial appearance, which included redundant skin folds on the eyelids and very soft earlobes, was reminiscent of classic EDS. The sclerae were white, and x-ray examination indicated that she had no signs of osteoporosis. The second patient was a 7-year-old boy who had been born near term and showed hypotonia in the first month of life. An operation was performed for strabismus. When examined at the age of 5 years, he had typical features of classic EDS, including soft and doughy skin, moderate skin hyperextensibility, and joint hyperlaxity. In addition, he had a pronounced tendency for splitting of the skin, easy bruising, and impaired wound healing. He also presented an unusual tenderness of the skin and soft tissues, evident when he was touched. He had pectus excavatum and flat feet. The sclerae were white, and radiographic examination showed no signs of osteoporosis. Both patients had an arg134-to-cys substitution in the COL1A1 gene. The arginine residue was highly conserved and localized to the X position of the Gly-X-Y triplet. As a consequence, intermolecular disulfide bridges were formed, resulting in type I collagen aggregates, which were retained in cells. Whereas substitutions of glycine residues in type I collagen invariably result in osteogenesis imperfecta, substitutions of nonglycine residues in type I collagen had not previously been associated with a human disease. In contrast, arg-to-cys substitutions in type II collagen had been identified in a variety of chondrodysplasias (e.g., see 120140.0003, 120140.0016, 120140.0018, 120140.0029).


.0060   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, 9-BP DUP
SNP: rs74315111, ClinVar: RCV000414247, RCV002260513, RCV002278640, RCV002523919, RCV003897833

Cabral et al. (2003) studied the effect of shifting the register of the collagen helix by a single Gly-X-Y triplet on collagen assembly, stability, and incorporation into fibrils and matrix. The studies utilized a triplet duplication in exon 44 of the COL1A1 gene that occurred in the cDNA and genomic DNA of 2 sibs with lethal OI type II (166210). The normal allele encodes 3 identical glycine-alanine-hydroxyproline (gly-ala-hyp) triplets at amino acids 868-876, whereas the mutant allele encodes 4. The register shift delayed helix formation, causing overmodification. Cabral et al. (2003) showed that N-propeptide cleavage in procollagen with the triplet duplication was slower than normal, indicating that the register shift persisted through the entire helix. The register shift also disrupted incorporation of mutant collagen into fibrils and matrix. The profound effects of shifting on chain interaction in the helix and on fibril formation correlated with the severe clinical consequences. The probands were the male and female offspring of healthy parents in their twenties. The mother was entirely normal by clinical history and physical examination but was shown to be a mosaic carrier with a low percentage of heterozygous mutant fibroblasts and leukocytes (10 and 15%, respectively).


.0061   OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A1, 3-BP DEL, 1964GGC
SNP: rs72651618, ClinVar: RCV000018886

In a family in which the mother and 4 children were affected with autosomal dominant osteogenesis imperfecta type IV (166220), Lund et al. (1996) identified an in-frame deletion of nucleotides 1964-1966 (GGC) from a series of 6 nucleotides (GAG/GCT) encoding codons 437 and 438 in exon 27 of the COL1A1 gene, resulting in the removal of an alanine residue at position 438 and a glu437-to-asp (E437D) substitution in the alpha-1 (I) collagen chain. The father was clinically normal and lacked the mutation, which was detected by restriction enzyme analysis in all affected family members. Clinical variation among affected members was considerable; the most consistent clinical features were reduced height and extraosseous manifestations of OI. The mother was 136 cm tall and her 19-year-old daughter 132 cm tall. A 28-year-old son was 137 cm tall but a 24-year-old son was 162 cm tall and a 31-year-old daughter 151 cm tall. All had white sclerae and dentinogenesis imperfecta. The heights of the mother, 2 daughters (31 and 19 years of age), and 2 sons (28 and 24 years of age), were 136, 151, 132, 137, and 162 cm, respectively. The mother and eldest sib had otosclerosis. The 24-year-old son was physically active and capable in sports, including contact sports, and his OI diagnosis was questioned by other members of the family.


.0062   OSTEOGENESIS IMPERFECTA, TYPE I

OSTEOGENESIS IMPERFECTA, TYPE IV, INCLUDED
COL1A1, IVS19DS, G-C, +1
SNP: rs66490707, ClinVar: RCV000018887, RCV000018888

Cabral and Marini (2004) described a family in which the mother was a mosaic carrier of an IVS19DS+1G-C mutation in the COL1A1 gene and had a phenotype compatible with OI type I (166200), whereas her 2 sons had moderately severe OI type IV (166220).


.0063   CAFFEY DISEASE

COL1A1, ARG836CYS
SNP: rs72653170, gnomAD: rs72653170, ClinVar: RCV000018889, RCV000420639, RCV000685879, RCV000763407

In affected individuals and obligate carriers from 3 unrelated families with Caffey disease (CAFYD; 114000), Gensure et al. (2005) identified heterozygosity for a 3040C-T transition in exon 41 of the COL1A1 gene, predicted to result in an arg836-to-cys (R836C) substitution within the triple-helical domain of the alpha-1 chain of type I collagen. None of the affected individuals or obligate carriers in any of the families had clinical signs of osteogenesis imperfecta, although some individuals did have joint hyperlaxity and hyperextensible skin. In 1 family the mutation was not found in the unaffected father, and in another family it was not found in the unaffected parents or sib of affected monozygotic twins in whom the mutation was assumed to have arisen de novo.

In 5 affected members of a Thai family with Caffey disease, Suphapeetiporn et al. (2007) identified heterozygosity for the R836C mutation in the COL1A1 gene.

Kamoun-Goldrat et al. (2008) identified heterozygosity for the R836C mutation in the COL1A1 gene in the pulmonary tissue of a fetus with a severe form of prenatal cortical hyperostosis from a terminated pregnancy at 30 weeks' gestation. The authors speculated that mutation in another gene might have also been involved.


.0064   COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 1

COL1A1, GLY13ASP
SNP: rs67828806, ClinVar: RCV000018891

In a patient wth combined osteogenesis imperfecta and Ehlers-Danlos syndrome (OIEDS1; 619115), Cabral et al. (2005) identified a gly13-to-asp (G13D) mutation in the COL1A1 gene. The authors showed that the disorder in this patient and 6 additional patients with a similar phenotype was due to glycine substitutions or an amino acid deletion within the N-anchor domain. Mutations within this stabilizing domain induced its reversible unfolding above 34 degrees centigrade (Makareeva et al., 2006).


.0065   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A1, GLY76GLU
SNP: rs72645320, ClinVar: RCV000018892

In a 13-year-old girl with severe osteogenesis imperfecta type III (OA3; 259420), Cabral et al. (2001) identified heterozygosity for a 761G-A transition in exon 11 of the COL1A1 gene, resulting in a gly76-to-glu (G76E) substitution. The mutant collagen helices have altered folding, and thermal denaturation curves demonstrated a decrease in helix stability. Cabral et al. (2001) stated that this was the first report of a glutamic acid substitution in the alpha-1(I) chain causing nonlethal osteogenesis imperfecta.


.0066   EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 1

COL1A1, IVS5AS, A-T, -2
SNP: rs72667019, ClinVar: RCV000018893

In a girl with severe arthrochalasia-type Ehlers-Danlos syndrome (EDSARTH1; 130060), Giunta et al. (2008) identified a heterozygous A-to-T transversion in the splice acceptor site of intron 5 of the COL1A1 gene, resulting in the skipping of exon 6. The mutation resulted in the deletion of amino acids from the N-proteinase cleavage site. The patient had bilateral hip dislocation, multiple subluxations of shoulders, elbows, and knees, arthrogryposis, clubfoot, and hypotonia.


.0067   BONE MINERAL DENSITY VARIATION QUANTITATIVE TRAIT LOCUS

COL1A1, 5-PRIME UTR, G-T, -1997 ({dbSNP rs1107946})
SNP: rs1107946, gnomAD: rs1107946, ClinVar: RCV000018881

See 120150.0051 and Jin et al. (2009).


.0068   BONE MINERAL DENSITY VARIATION QUANTITATIVE TRAIT LOCUS

COL1A1, 5-PRIME UTR, INDEL T, -1663 ({dbSNP rs2412298})
SNP: rs11327935, rs2412298, gnomAD: rs11327935, rs2412298, ClinVar: RCV000018883

See 120150.0051 and Jin et al. (2009).


.0069   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, 1-BP DEL, 4247C
SNP: rs398122835, ClinVar: RCV000034354

Takagi et al. (2011) reported a sporadic case of what they termed 'classic OI IIC' (see 166210) in a Japanese patient in whom they identified a 1-bp deletion (4247delC) in the C-propeptide region of the COL1A1 gene, resulting in a frameshift.


.0070   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A1, ALA1387VAL
SNP: rs397514672, ClinVar: RCV000034355

In 2 Japanese sibs with features of 'OI IIC' (see 166210) but less distortion of the tubular bones (OI dense bone variant), Takagi et al. (2011) identified a 4160C-T transition in the C-propeptide region of the COL1A1 gene, resulting in an ala1387-to-val (A1387V) substitution. Familial gene analysis revealed somatic mosaicism of the mutation in the clinically unaffected father of the sibs, whereas their mother and healthy older sister did not have the mutation.


.0071   COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 1

COL1A1, ARG888CYS
SNP: rs72654799, gnomAD: rs72654799, ClinVar: RCV000485287, RCV000794277, RCV001270299, RCV002323823

In 4 patients in a small pedigree with combined osteogenesis imperfecta and Ehlers Danlos syndrome-1 (OIEDS1; 619115), Cabral et al. (2007) identified heterozygosity for a c.3196C-T transition (c.3196C-T, NM_000088.3) in the COL1A1 gene, resulting in an arg888-to-cys (R1066C) substitution in the Y position of one of the Gly-X-Y triplets that compose the collagen helix. The substitution in the Y position was shown to result in less delay in helix formation than would have been expected for a glycine substitution. Disulfide-bonded dimers of alpha(I) chains formed inefficiently in helices with 2 mutant chains; however, secretion from cells was normal. Formation of disulfide dimers at position 888 resulted in helix kinking, with resulting decreased helix stability and propagation of altered secondary structure along the remaining helix.


.0072   COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 1

COL1A1, GLY188ASP
SNP: rs1114167408, ClinVar: RCV000490656, RCV001270300, RCV002350082

In a patient with combined osteogenesis imperfecta and Ehlers Danlos syndrome-1 (OIEDS1; 619115), Malfait et al. (2013) identified a heterozygous c.563A-G transition (c.563A-G, NM_000088.3) in exon 7 of the COL1A1 gene, resulting in a gly188-to-asp (G188D) substitution.


.0073   OSTEOGENESIS IMPERFECTA, TYPE II

COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 1, INCLUDED
COL1A1, 9-BP DEL, NT3150
SNP: rs74315111, ClinVar: RCV000413092, RCV000623236, RCV001270301, RCV002278641, RCV002524640, RCV003422381

Osteogenesis Imperfecta, Type II

In an infant with lethal osteogenesis imperfecta type II (OI2; 166210), Hawkins et al. (1991) identified a 9-bp deletion in the COL1A1 gene, which was not present in the parents. The mutation was said to occur within a repeating sequence of exon 43, causing the loss of 1 of 3 consecutive gly-ala-pro triplets at positions 868-876, but does not disrupt the Gly-X-Y sequence.

Combined Osteogenesis Imperfecta and Ehlers-Danlos Syndrome 1

In a patient with combined osteogenesis imperfecta and Ehlers-Danlos syndrome-1 (OIEDS1; 619115), Symoens et al. (2017) identified a heterozygous in-frame 9-bp deletion (c.3150_3158del) in exon 44 of the COL1A1 gene, resulting in deletion of 3 amino acids (Ala1053_Gly1055del). This mutation was seen in 9% of DNA derived from patient fibroblasts and in none of the DNA derived from blood. Symoens et al. (2017) stated that this was the same mutation identified by Hawkins et al. (1991) in a patient with lethal OI and concluded that mosaicism might have been responsible for the mild symptoms in their patient.


See Also:

Bateman et al. (1987); Bonadio et al. (1988); Chu et al. (1985); Cole et al. (1990); Cole et al. (1987); Dayhoff (1972); Solomon et al. (1984); Solomon et al. (1984); Thompson et al. (1987)

REFERENCES

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Contributors:
Sonja A. Rasmussen - updated : 12/10/2020
Nara Sobreira - updated : 4/2/2013
Nara Sobreira - updated : 4/11/2011
George E. Tiller - updated : 6/23/2010
Patricia A. Hartz - updated : 5/5/2010
Nara Sobreira - updated : 6/17/2009
Ada Hamosh - updated : 7/9/2008
Cassandra L. Kniffin - updated : 6/18/2008
Marla J. F. O'Neill - updated : 1/24/2008
Marla J. F. O'Neill - updated : 1/2/2008
John A. Phillips, III - updated : 1/2/2008
Cassandra L. Kniffin - updated : 9/21/2007
Cassandra L. Kniffin - updated : 8/29/2007
Cassandra L. Kniffin - updated : 5/17/2007
Marla J. F. O'Neill - updated : 9/29/2006
Anne M. Stumpf - updated : 6/13/2006
Victor A. McKusick - updated : 6/6/2006
Marla J. F. O'Neill - updated : 5/20/2005
Victor A. McKusick - updated : 2/4/2005
Victor A. McKusick - updated : 12/9/2004
Ada Hamosh - updated : 6/11/2004
Marla J. F. O'Neill - updated : 6/2/2004
Victor A. McKusick - updated : 4/21/2004
Jane Kelly - updated : 8/19/2003
Victor A. McKusick - updated : 5/16/2003
Victor A. McKusick - updated : 1/30/2003
Victor A. McKusick - updated : 8/9/2002
Victor A. McKusick - updated : 2/15/2002
Victor A. McKusick - updated : 4/13/2000
Victor A. McKusick - updated : 1/11/2000
John A. Phillips, III - updated : 11/29/1999
Victor A. McKusick - updated : 4/15/1998
Victor A. McKusick - updated : 3/13/1998
Victor A. McKusick - updated : 12/11/1997
Victor A. McKusick - updated : 6/23/1997
Victor A. McKusick - updated : 6/18/1997
Victor A. McKusick - updated : 5/8/1997
Jennifer P. Macke - updated : 4/14/1997
Victor A. McKusick - updated : 3/21/1997
Moyra Smith - updated : 11/12/1996
Orest Hurko - updated : 11/6/1996
Alan F. Scott - updated : 2/20/1996

Creation Date:
Victor A. McKusick : 6/4/1986

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wwang : 5/23/2005
terry : 5/20/2005
wwang : 2/16/2005
wwang : 2/10/2005
terry : 2/4/2005
tkritzer : 1/20/2005
tkritzer : 1/6/2005
terry : 12/9/2004
alopez : 6/15/2004
terry : 6/11/2004
carol : 6/7/2004
terry : 6/2/2004
tkritzer : 4/23/2004
terry : 4/21/2004
carol : 12/26/2003
carol : 8/19/2003
carol : 8/1/2003
mgross : 6/23/2003
tkritzer : 6/4/2003
tkritzer : 5/30/2003
terry : 5/16/2003
alopez : 1/31/2003
terry : 1/30/2003
carol : 9/18/2002
tkritzer : 8/15/2002
tkritzer : 8/13/2002
terry : 8/9/2002
cwells : 2/25/2002
cwells : 2/20/2002
terry : 2/15/2002
carol : 2/20/2001
terry : 1/12/2001
carol : 5/25/2000
carol : 5/12/2000
terry : 4/13/2000
mgross : 2/3/2000
terry : 1/11/2000
alopez : 11/29/1999
psherman : 11/29/1999
mgross : 11/24/1999
dkim : 12/15/1998
dkim : 12/10/1998
dkim : 12/9/1998
terry : 6/18/1998
terry : 5/29/1998
terry : 4/17/1998
terry : 4/15/1998
alopez : 3/17/1998
terry : 3/13/1998
psherman : 3/13/1998
terry : 3/6/1998
mark : 12/20/1997
terry : 12/11/1997
mark : 7/15/1997
jenny : 6/27/1997
alopez : 6/27/1997
terry : 6/23/1997
alopez : 6/21/1997
mark : 6/18/1997
alopez : 5/16/1997
mark : 5/8/1997
alopez : 5/8/1997
alopez : 5/7/1997
alopez : 5/5/1997
alopez : 4/14/1997
terry : 3/21/1997
terry : 3/17/1997
terry : 1/27/1997
jamie : 1/21/1997
jamie : 1/21/1997
mark : 1/15/1997
jenny : 1/14/1997
mark : 11/12/1996
mark : 11/6/1996
terry : 10/23/1996
mark : 10/5/1996
terry : 6/7/1996
terry : 5/30/1996
terry : 3/29/1996
mimman : 3/27/1996
mark : 3/4/1996
mark : 2/27/1996
terry : 2/20/1996
mark : 2/5/1996
terry : 2/1/1996
mark : 10/22/1995
carol : 3/19/1995
terry : 11/1/1994
davew : 8/5/1994
warfield : 4/7/1994
mimadm : 2/11/1994