* 120160

COLLAGEN, TYPE I, ALPHA-2; COL1A2


Alternative titles; symbols

COLLAGEN OF SKIN, TENDON, AND BONE, ALPHA-2 CHAIN


HGNC Approved Gene Symbol: COL1A2

Cytogenetic location: 7q21.3     Genomic coordinates (GRCh38): 7:94,394,895-94,431,227 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
7q21.3 {Osteoporosis, postmenopausal} 166710 AD 3
Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2 619120 AD 3
Ehlers-Danlos syndrome, arthrochalasia type, 2 617821 AD 3
Ehlers-Danlos syndrome, cardiac valvular type 225320 AR 3
Osteogenesis imperfecta, type II 166210 AD 3
Osteogenesis imperfecta, type III 259420 AD 3
Osteogenesis imperfecta, type IV 166220 AD 3

TEXT

Cloning and Expression

De Wet et al. (1987) isolated 60 kb of cloned DNA containing the entire COL1A2 gene and 22 kb of flanking sequences. Like the homologous avian gene, the 1,366 amino acid residues of the human prepropolypeptide chain are encoded by 52 exons. Analysis of the 5-prime and 3-prime untranslated regions conclusively established the nature of 5 polymorphic mRNA transcripts. The exons are equally distributed as follows: 6 in the N-propeptide domain, 42 in the alpha-chain region, and 4 in the C-propeptide domain. Kuivaniemi et al. (1988) characterized a full-length cDNA clone for the COL1A2 gene.

Into 1-cell mouse embryos, Khillan et al. (1986) injected a hybrid gene made from DNA 2 kb upstream from the COL1A2 gene and the bacterial gene for chloramphenicol acetyltransferase (CAT). They established a number of transgenic mouse strains and found that the promoter contained information for stage- and tissue-specific expression of the COL1A2 gene. For example, the level of CAT activity was higher in extracts of tail (a structure rich in tendon) than in any other tissue tested.


Mapping

Junien et al. (1982) assigned the gene for the alpha-2 polypeptide of collagen I to chromosome 7 by means of molecular hybridization in subclones of somatic cell hybrids, using a cDNA probe. Other chromosomes, including 17, could be excluded. Using an EcoRI fragment cloned from the COL1A2 gene in somatic cell hybrids containing an X/7 translocation, Solomon et al. (1983) concluded that the alpha-2 gene of type I collagen is in the 7pter-q22 portion of chromosome 7. By use of a cDNA probe in cells of a patient trisomic for 7q, Junien et al. (1984) narrowed the assignment to 7q21. 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. Kere et al. (1989) described the linkage relationships of the COL1A2 locus and the erythropoietin (EPO) and plasminogen activator type I (PLANH1). Moreover, the same authors used pulsed field gel electrophoresis technology to construct a 3-megabase physical map including COL1A2 and 3 anonymous DNA segments.

Shupp Byrne and Church (1983) assigned the genes for the alpha-1 and the alpha-2 chains of type I collagen to mouse chromosome 16. Munke et al. (1986) corrected the assignment of Cola-1 to mouse chromosome 11 where it formed part of an evolutionarily conserved linkage group with homologous genes on human chromosome 17. Similarly, by a combination of somatic cell hybrid analysis and genetic linkage, Irving et al. (1989) demonstrated that the Cola-2 gene is located on mouse chromosome 6 where it is linked to the MET protooncogene locus.


Molecular Genetics

Amino Acid Numbering System for COL1A2

Conventional numbering for the alpha-2(I) amino acid residues involves assigning number 1 to the first glycine of the triple-helical domain. This numbering system is used in the list of allelic variants below.

Osteogenesis Imperfecta

In a patient with osteogenesis imperfecta (OI), the son of third-cousin parents, Myers et al. (1985) found a homozygous frameshift mutation in the portion of the COL1A2 gene coding the COOH-propeptide. The type I procollagen secreted by his fibroblasts contained only pro-alpha-1(I) homotrimers, although pro-alpha-2(I) chains were found intracellularly (Deak et al., 1983). Dickson et al. (1984) used nuclease S1 mapping to demonstrate the homozygous defect in the patient's mRNA coding for the pro-alpha-2(I) COOH-propeptide and a heterozygous pattern in the asymptomatic parents. Clinically, the patient's OI was moderate in severity and, according to other reports, was accompanied by blue sclerae. This is recessive inheritance of moderate OI. The reports by Myers et al. (1985), Pope et al. (1985), and Nicholls et al. (1979, 1984) concern the same patient.

Wallis et al. (1986) concluded from linkage studies using 3 DNA polymorphisms associated with the COL1A2 gene that the defect in a 'significant proportion of cases' of osteogenesis imperfecta type I is located in that gene. They quoted others as showing that mutations in the COL1A2 gene can produce not only OI type I but also OI types II, III and IV.

Knisely et al. (1988) found a karyotypic abnormality involving the COL1A2 gene in an infant who died of complications of osteogenesis imperfecta at 22 days of age. The infant had an inversion, inv(7)(p13q22). The mother carried the same inversion. The authors suggested that damage to 1 COL1A2 gene caused by the inversion might have contributed to disease in the infant if a mutation affecting the other allele was present. Knisely et al. (1989) reported that the type I procollagen chains were completely normal in both parents of the case reported by Knisely et al. (1988), which led them to conclude that the rearrangement involving chromosome 7 had nothing to do with the mutation in the COL1A2 gene in the child.

Spotila et al. (1992) identified partial isodisomy for maternal chromosome 7 in a 30-year-old man who was 143.7 cm tall and weighed 36.6 kg. He had greatly reduced bone mineral density values (below the 2nd percentile for his age and gender at all sites measured). The sclerae were slightly blue; hearing was within normal limits. Uniparental disomy (UPD) for chromosome 7 had been reported previously in 2 unrelated probands discovered because of cystic fibrosis. The proband of Spotila et al. (1991) was identified initially during a screening of relatives of a woman with postmenopausal osteoporosis resulting from a gly661-to-ser (120160.0030) mutation of the COL1A2 gene. The woman was heterozygous for the mutation as were a cousin and 2 of her 3 sons. The third son, subsequently shown to have UPD, was apparently homozygous, although his father had only the normal allele. Like the previously reported cases of maternal disomy for chromosome 7, the proband had retarded growth and short stature. At 5 loci, of which the mother and father did not share alleles, the proband had inherited only the maternal allele. He was homozygous for all informative loci examined with the exception of 1 locus on the proximal short arm of chromosome 7. Thus, the UPD was probably the result of fertilization of a maternal gamete disomic for chromosome 7, with either a nullisomic sperm or a normal sperm followed by loss of the paternal homolog.

Pepe (1993) described an ACT trinucleotide repeat VNTR within intron 12 of the COL1A2 gene. Six alleles were detected with repeats varying from 6 to 12 times. Because of a high level of heterozygosity, the use of this polymorphism in the diagnosis of osteogenesis imperfecta by the linkage principle and in forensic applications was suggested. Furthermore, the possibility that instability of the trinucleotide repeat might lead to abnormalities such as in the unexplained collagenopathies or suspected collagenopathies was raised.

De Paepe et al. (1997) reported 2 sibs with severe, progressively deforming osteogenesis imperfecta (OI type III; 259420) and homozygosity by descent for a gly751-to-ser substitution (120160.0039) in the alpha-2(I) collagen chain due to a G-to-A transition in the COL1A2 gene. The parents, who were first cousins, and 2 elder sibs were heterozygous for the mutation and presented mild clinical manifestations of OI. Collagen studies on cultured fibroblasts from 1 of the probands showed that cells from the homozygote produced only mutant, unstable collagen I, whereas cells from the heterozygote produced both normal and mutant collagen I.

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.

Trummer et al. (2001) described a gly238-to-cys mutation in the COL1A2 gene leading to severe osteogenesis imperfecta type III (259420). This was said to be the most N-terminal cysteine substitution in the gene reported up to that time. A gly238-to-ser substitution had been observed 5 times in unrelated patients showing a highly variable expression of OI (Dalgleish, 1998).

Ehlers-Danlos Syndrome, Arthrochalasia Type, 2

From studies of type I collagen in a patient with Ehlers-Danlos syndrome type VIIB (EDSARTH2; 617821), Eyre et al. (1985) determined that 1 allele of the COL1A2 gene carried a de novo mutation (120160.0001) that results in deletion of 15 to 20 residues in the junction domain that spans the N-propeptidase cleavage site and the N-telopeptide cross-linking sequence.

Minor et al. (1986) observed one case of EDS VII in which a structural abnormality of the alpha-2 chain of type I collagen was responsible for resistance to cleavage of procollagen.

By electrophoretic studies of collagen excreted from cultured skin fibroblasts, Tsukahara et al. (1988) found an alpha-2 chain with an anomaly of small molecular size in mother and daughter. Only the daughter showed clinical abnormality: loose, wrinkled skin and other features of cutis laxa, together with fragility, bruisability, and hyperextensibility of the skin, with poor wound healing and 'cigarette paper' scars. The father and another daughter were normal clinically.

In a patient with EDS VIIB, Weil et al. (1988) identified a heterozygous mutation in the COL1A2 gene (120160.0002) that results in the skipping of exon 6 and elimination of the N-proteinase cleavage site necessary for proper collagen processing.

In a patient with EDS VIIB, Weil et al. (1989) identified a de novo heterozygous mutation in the COL1A2 gene (120160.0003) that deletes the cleavage site necessary for collagen processing.

In a patient with EDS VIIB, Nicholls et al. (1991) identified a heterozygous mutation in the COL1A2 gene (120160.0021).

In affected members of 6 unrelated families with EDSARTH2, Byers et al. (1997) identified heterozygosity for mutations in the COL1A2 gene (see, e.g., 120160.0042).

Ehlers-Danlos Syndrome, Cardiac Valvular Type

Sasaki et al. (1987) described a form of EDS with deficiency of pro-alpha-2 chains of type I procollagen. The patient was a 30-year-old man known to have had aortic regurgitation for 3 years. Since infancy he had suffered from hypermobility of the joints, hyperextensibility of the skin, and prolongation of wound healing. Aortic valve replacement was performed. Histologically, the aortic valve showed abundant alcian blue-positive myxomatous matrix accompanied by scattered mesenchymal cells instead of normal collagen fibers with fibroblasts. Similar but less conspicuous changes were found in the aorta itself. A biopsy specimen of the skin showed thin, somewhat fragmentary collagen fibers, while elastic fibers appeared normal. Analysis of collagen produced by cultured fibroblasts showed a lack of detectable pro-alpha-2 chains of type I procollagen. The intracellular degradation rate of newly synthesized collagen was higher than that of normal cells, resulting in the reduction of net collagen production.

Schwarze et al. (2004) described 3 unrelated patients with a rare, recessively inherited form of EDS characterized by joint hypermobility, skin hyperextensibility, and cardiac valvular defects (EDSCV; 225320); in 2 of them, one of whom had previously been reported by Hata et al. (1988) and Kojima et al. (1988), COL1A2 mRNA instability resulted from compound heterozygosity for splice site mutations in the COL1A2 gene (120160.0045-120160.0046 and 120160.0047-120160.0048, respectively), and, in the third, it resulted from homozygosity for a nonsense mutation (E1201X; 120160.0051). The splice site mutations led to use of cryptic splice donor sites, creation of a downstream premature termination codon, and highly unstable mRNA. In the wildtype allele, the 2 introns in which these mutations occurred, IVS11 and IVS24, were usually spliced slowly in relation to their respective immediate upstream introns. In the mutant alleles, the upstream intron was removed, so that exon skipping could not occur. In the context of the mutation in IVS24, computer-generated folding of a short stretch of mRNA surrounding the mutation site demonstrated realignment of the relationships between the donor and acceptor sites that could facilitate use of a cryptic donor site. The findings suggested that the order of intron removal is an important variable in prediction of the outcome of mutation at splice sites and that folding of the nascent mRNA could be 1 element that contributes to determination of order of splicing. The complete absence of pro-alpha-2(I) chains had the effect of producing cardiac valvular disease without bone involvement.

Byers (2002) observed compound heterozygosity for 2 donor splice site mutations in the COL1A2 gene that resulted in failure to produce pro-alpha-2 chains of type I collagen (120160.0045, 120160.0046). At the age of 45 years, the patient had significant aortic and mitral valvular disease and had borderline dilatation of the root of the aorta.

In 2 sisters, born to apparently unrelated parents in a small town in southern Italy, with EDSCV, Guarnieri et al. (2019) identified homozygosity for the nonsense mutation in the COL1A2 gene (120160.0051) that was previously identified by Schwarze et al. (2004). The mutation, which was found by screening the coding regions of 20 genes involved in EDS, was present in heterozygous state in the parents. The variant was not found in large population databases.

Combined Osteogenesis Imperfecta and Ehlers-Danlos Syndrome 2

Nathanson et al. (1997) described a family with combined osteogenesis imperfecta and Ehlers-Danlos syndrome-2 (OIEDS2; 619120) due to a splice site mutation in the COL1A2 gene (120160.0041). Byers (2002) hypothesized that the phenotypic outcome from failure to incorporate pro-alpha-2 chains into type I procollagen molecules may be explained by a small amount of abnormal pro-alpha-2 chains made in the cases with OI that gets incorporated into molecules and alters mineralization.

Multiexon duplication or deletion in type I collagen genes has rarely been rarely observed and generally results in a severe or lethal phenotype. In a patient with OIEDS2, Raff et al. (2000) identified a heterozygous 13.5-kb duplication involving 20 exons in the COL1A2 gene (120160.0043), resulting in an additional 477 amino acids in the triple-helical domain. The abnormal molecule was synthesized and secreted by cultured dermal fibroblasts in a normal fashion. Electron microscopy of dermal tissue revealed small but otherwise near-normal collagen fibrils. The gene duplication occurred by mitotic sister chromatid exchange in the mother, who was mosaic for the duplication allele. Examination of the abnormal sequence suggested a means by which the duplicated molecule could be processed and properly incorporated into mature collagen fibrils.

Nicholls et al. (2001) described a 9-year-old girl, born of consanguineous parents, who was homozygous for a splice site mutation in the COL1A2 gene (120160.0049) that yielded a nonfunctional alpha-2 procollagen chain and an OIEDS clinical phenotype. The mother, who showed some joint laxity, and a younger sister were carriers of the mutation; the father was not available for testing.

Malfait et al. (2013) sequenced the COL1A1 and COL1A2 genes in 7 patients with OIEDS1 (619115) or OIEDS2 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; of the 5 mutations in COL1A2, 3 were exon skipping (see, e.g., 120160.0056) and 2 were missense (see, e.g., 120160.0057). The mutations affected the rate of type I collagen N-propeptide cleavage and disturbed normal collagen fibrillogenesis.

Reviews

Kuivaniemi et al. (1997) tabulated all reported mutations of the COL1A2 gene as well as those of 6 other collagen genes.

Dalgleish (1997) described a mutation database for the COL1A1 and COL1A2 genes accessible on the World Wide Web. See also Dalgleish (1998).


Genotype/Phenotype Correlations

Superti-Furga et al. (1989) reported a family in which osteogenesis imperfecta linked to COL1A2 and associated with a structural defect in the triple-helical region of the alpha-2 chains resulted in a very mild clinical picture in some individuals in whom the diagnosis of OI had not been made, mainly because of the lack of fractures, and severe OI in others. All affected members showed dentinogenesis imperfecta and myopia. The findings confirmed that mutations in the triple-helical region of the alpha-2 chains produce a milder phenotype than do corresponding mutations in the alpha-1 chains, but indicated that, in addition to defects in the type I collagen molecule, other factors must modulate the degree of bone involvement. In 4 out of 60 persons with deforming (nonlethal) varieties of osteogenesis imperfecta, Cohn and Byers (1991) demonstrated alpha-2 chains with a cysteine residue in the triple helix, a domain from which it is normally excluded. The clinical differences among these 4 individuals and the heterogeneity in the locations of the cysteine residues suggested that the position of the substitution within the chain is important in determining the clinical phenotype.

Malfait et al. (2006) found 8 reports of complete deficiency of the alpha-2 chains of type I collagen due to homozygosity or compound heterozygosity for a nonfunctional COL1A2 gene; see reports by Deak et al. (1983), Hata et al. (1988), Nicholls et al. (1979), Nicholls et al. (1984), Nicholls et al. (2001), Pihlajaniemi et al. (1984), Sasaki et al. (1987), and Schwarze et al. (2004). The clinical features of these patients, however, were strikingly variable, ranging from severe osteogenesis imperfecta to a mild EDS/OI-like phenotype, and associated in some adult patients with severe cardiac valvular abnormalities (EDSCV; 225320), necessitating cardiac surgery. Malfait et al. (2006) recorded the clinical features of a 6-year-old boy in whom complete lack of alpha-2 chains of type I collagen (see 120160.0052) was associated with a phenotype reminiscent of mild hypermobility EDS (130020). Careful cardiac follow-up with ultrasonography was highly recommended because of the risk for cardiac valvular problems developing in adulthood. The 6-year-old subject reported by Malfait et al. (2006) already showed abnormal mitral valve bulging. Malfait et al. (2006) suggested a possible mechanism for the variable phenotype in patients with complete deficiency of the alpha-2 chain. In most cases, the underlying COL1A2 mutations result in nonsense-mediated RNA decay (NMD) and a loss-of-function effect. The phenotypic consequences are those of a form of EDS characterized by hypermobility in childhood and complicated by cardiac valve disease in adulthood. On the other hand, COL1A2 mutations that do not result in NMD produce a gain-of-function effect with the production of abnormal collagen type I chains that disturb interaction with the normal collagen chains and lead to a severe OI phenotype.

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.

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 0, 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.

Faqeih et al. (2009) reported 3 unrelated patients with OI type III, brachydactyly, and intracranial hemorrhage, 1 of whom was previously described by Cole and Lam (1996), who all had glycine mutations involving exon 49, in the most C-terminal part of the triple-helical domain of COL1A2 (120160.0037, 120160.0054, and 120160.0055, respectively). Faqeih et al. (2009) suggested that mutations in this region of COL1A2 carry a high risk of abnormal limb development and intracranial bleeding.

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 sclerae, 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 amino-terminal end of the collagen type I triple helix had blue sclerae 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 sclerae, respectively.


ALLELIC VARIANTS ( 57 Selected Examples):

.0001 EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2

COL1A2, EX6DEL
   RCV000018772

From studies of type I collagen in a patient with Ehlers-Danlos syndrome type VIIB (EDSARTH2; 617821), Eyre et al. (1985) determined that 1 allele of the COL1A2 gene carried a de novo mutation that resulted in deletion of 15 to 20 residues in the junction domain that spans the N-propeptidase cleavage site and the N-telopeptide cross-linking sequence.


.0002 EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2

COL1A2, IVS6DS, T-C, +2
  
RCV000018773...

In a Libyan patient with Ehlers-Danlos syndrome type VIIB (EDSARTH2; 617821) reported by Steinmann et al. (1985) and Wirtz et al. (1987), Weil et al. (1988) identified a heterozygous T-to-C transition in at the splice donor site of intron 6 of the COL1A2 gene, resulting in the skipping of exon 6. In this patient, Wirtz et al. (1987) had identified a deletion of 18 amino acids of the N-telopeptide of the pro-alpha-2 chain of type I collagen.

Ho et al. (1994) observed the same mutation in a Chinese patient with EDS VIIB.


.0003 EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2

COL1A2, IVS6DS, G-A, -1
  
RCV000018774...

In a patient with Ehlers-Danlos syndrome type VIIB (EDSARTH2; 617821) previously reported by Lichtenstein et al. (1973) and Steinmann et al. (1980), Weil et al. (1989) identified a de novo heterozygous G-to-A transition in the last nucleotide of exon 6 of the COL1A2 gene, resulting in the skipping of exon 6 and deletion of the cleavage site necessary for proper collagen processing. The expression of the alternative splicing in this patient was found to be temperature-dependent; cellular studies showed that missplicing was effectively abolished at 31 degrees C and gradually increased to 100% at 39 degrees C. In contrast, in the patient who had a substitution in the obligatory GT dinucleotide of the 5-prime splice site of intron 6 of COL1A2 (120160.0002), complete outsplicing of exon 6 sequences was found at all temperatures. This mutation is identical to that found in COL1A1 (120150.0026).


.0004 OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A2, GLY1012ARG
  
RCV000018775...

In a patient with osteogenesis imperfecta of Sillence type IV (166220), Wenstrup et al. (1988) found an arginine for glycine substitution at position 1012 (G1012R), the last triple-helical glycine. Increased posttranslational modification along the entire triple-helical domain resulted.


.0005 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, EX1, FS
  
RCV000018776

In a patient with osteogenesis imperfecta of Sillence type III (259420), Pihlajaniemi et al. (1984) demonstrated a 4-nucleotide frameshift deletion in exon 1 which instigated the use of a new termination codon 4 nucleotides 3-prime to the original site.


.0006 OSTEOGENESIS IMPERFECTA, MILD

COL1A2, EX11DEL
  
RCV000018777...

In a boy with 'atypical' OI and his asymptomatic mother, Kuivaniemi et al. (1988) found deletion of 19 bp at the junction of IVS 10 and exon 11 causing abnormal splicing between exons 10 and 12 and a shortened pro-alpha-2 chain of type I collagen.


.0007 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, DEL 7EX, CODONS 586-765
   RCV000018778

Willing et al. (1988) characterized a de novo 4.5-kb deletion in the paternally derived COL1A2 allele found in a patient with perinatal lethal osteogenesis imperfecta (166210). The intron-to-intron deletion removed the 7 exons that encode residues 586-765 of the triple-helical domain of the chain. A block in secretion appeared to result from improper assembly of the triple helix. The lethal effect may have been due in part to decreased secretion of normal collagen and secretion of a small amount of abnormal collagen that disrupts matrix formation.


.0008 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY907ASP
  
RCV000018779...

In an infant with a lethal variety of osteogenesis imperfecta (166210), Baldwin et al. (1989) found a G-to-A change that converted glycine-907 to aspartic acid (G907D). The change resulted in decreased thermal stability of type I collagen synthesized by the patient's fibroblasts.


.0009 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, EX33DEL
  
RCV000018780

In a lethal form of osteogenesis imperfecta (166210), Baldwin et al. (1988) found deletion of 54 bp corresponding to exon 33.


.0010 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY547ASP
  
RCV000018781

By RNA sequence analysis, Bonadio et al. (1988) demonstrated heterozygosity for a glycine-to-aspartic acid substitution at position 547 (G547D) in a case of perinatal lethal osteogenesis imperfecta (166210).


.0011 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY865SER
  
RCV000018782

Using the Cotton chemical cleavage method to localize and characterize single bp mRNA mutations, Lamande et al. (1989) demonstrated substitution of serine for glycine at position 865 (G865S).


.0012 MOVED TO 120160.0020


.0013 OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A2, GLY646CYS
  
RCV000018783

Wenstrup et al. (1990) found a substitution of cystine for glycine-646 (G646C) in a family with mild osteogenesis imperfecta. Wenstrup et al. (1993) described the mutation in 2 families with type IV osteogenesis imperfecta (OI4; 166220).


.0014 OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A2, EX26DEL
   RCV000018784

In a family with mild osteogenesis imperfecta (166220), Wenstrup et al. (1990) found that alpha-2(I) mRNA was shortened by the 54 bp coded by exon 26.


.0015 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY976ASP
   RCV000018785

Byers (1990) provided information on this mutation.


.0016 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY805ASP
  
RCV000018786

Byers (1990) provided information on this mutation.


.0017 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, GLY259CYS
  
RCV000018787

Byers (1990) provided information on this mutation as a cause of osteogenesis imperfecta type II (166210). Wenstrup et al. (1993) reported this mutation in a single family. The phenotype was said to be 'moderately severe' or 'severe deforming,' suggesting that this may be osteogenesis imperfecta type III (OI3; 259420).


.0018 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, EX28DEL
  
RCV000018788

In a case of type II osteogenesis imperfecta (OI2; 166210), Tromp and Prockop (1988) found that the previously demonstrated shortened pro-alpha-2 chain of type I collagen resulted from deletion of exon 28 which in turn resulted from substitution of G for A at the 3-prime end of intron 27.


.0019 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY472CYS
  
RCV000018789

Edwards et al. (1990) demonstrated somatic mosaicism for this mutation in the father of 2 children with lethal osteogenesis imperfecta (OI2; 166210), each from a different partner. The mutation was found in 33% of sperm, 67% of lymphocytes, and 100% of dermal fibroblasts. The authors hypothesized that the mutation occurred very early in development in a cell that gave rise to both ectodermal and mesodermal cell lineages. Edwards et al. (1992) stated that despite the high level of mosaicism detected in somatic tissues, the only phenotypic manifestation of OI in the proband (the father) was that he was shorter than his unaffected male relatives and had mild dentinogenesis imperfecta. Thermal stability of type I collagen molecules containing the substitution was decreased but to a lesser extent than that for a nonlethal gly259-to-cys (G259C) substitution of the alpha-2(I) (120160.0017) chain, indicating that this measure of molecular stability may be of limited use in explaining the pathogenesis of OI. Edwards et al. (1992) stated that this was the second family in which recurrence of lethal OI had resulted from parental germline mosaicism for a dominant lethal mutation and the fourth family in which there was molecular evidence of parental mosaicism for a mutation that produced lethal OI. The mosaic parent in all 4 families was also mosaic for the mutation in somatic tissues. Since the mutation was detected in blood from all 4 mosaic individuals but not in DNA from cultured fibroblasts in one, blood may be the best parental somatic tissue to examine for mutation found in a sporadic affected infant.


.0020 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

COL1A2, ARG618GLN
  
RCV000018790...

This variant, formerly titled MARFAN SYNDROME, ATYPICAL or MARFAN SYNDROME VARIANT, has been reclassified based on the findings of Forlino et al. (1998) and Vomund et al. (2004).

Byers et al. (1981) found 2 species of the alpha-2 chain of type I collagen in 1 of 11 Marfan patients studied; one of the alpha-2 chains was normal whereas the other contained a 20-amino acid insertion in the amino-terminal propeptide. This alteration in chain size probably accounted for the 5- to 10-fold increase in collagen extraction into nondenaturing solvents from this patient's skin compared to controls. The patient of Byers et al. (1981) was a 39-year-old woman who had unaffected parents and 2 unaffected sibs. Features were equinovarus deformities of both feet at birth; arachnodactyly first noted at age 9 and lumbar scoliosis and heart murmur first noted at age 10. Aortic and mitral regurgitation with dilated root of the aorta prompted surgical replacement of the aortic valve and a portion of the ascending aorta at age 37. Her height was 164.5 cm, span 178 cm, upper segment to lower segment ratio 0.80. No lens dislocation was detected. She showed bluish-gray sclerae and mild myopia. Mild pectus carinatum was present, as well as long slender limbs with increased mobility in all joints except the fourth and fifth fingers which bilaterally showed marked camptodactyly. Henke et al. (1985) suggested that there was a 38-basepair insertion in the COL1A2 gene that caused the Marfan syndrome. Dalgleish et al. (1986) found, however, that this is a common polymorphism of the COL1A2 gene. Among 28 normal persons, 12 were homozygous for the large oligo, 12 were heterozygous, and 4 were homozygous for the small oligo. Phillips et al. (1990) further studied the patient and demonstrated a single base change, resulting in substitution of arginine-618 by glutamine at the Y position of a Gly-X-Y repeat. Family studies indicated that the substitution was inherited from the patient's father who also produced abnormally migrating pro-alpha-2(I) collagen chains and shared some of the abnormal skeletal features. The single base change at nucleotide 2258 resulted in a new Bsu36I (SauI, MstII) restriction site detectable in genomic DNA by Southern blot analysis when probed with a COL1A2 fragment. Analyses of 103 chromosomes in 52 controlled individuals were negative for the new site, indicating that the substitution is not a common polymorphism.

Forlino et al. (1998) identified the R618Q variant and a gly421-to-asp mutation (G421D; 120160.0053) in cis in a patient with lethal osteogenesis imperfecta (166210). The patient's unaffected father also carried the R618Q variant. Forlino et al. (1998) determined that the R618Q variant resulted in only mild electrophoretic delay. They suggested that G421D was the causative mutation and that R618Q is a rare variant.

Vomund et al. (2004) analyzed the helical stability and fibrillar assembly of type I collagen from cultured dermal fibroblasts of controls and 2 unrelated individuals heterozygous for the R618Q variant. They found that the thermal stability of the R618Q-containing collagen molecules did not differ statistically from control molecules, but that the diameter of assembled R618Q-containing collagen fibrils was approximately 20% of control collagen fibrils. Vomund et al. (2004) suggested that while the R618Q variant does not impact triple-helical stability, it does impact collagen fibril assembly and may therefore have a role as a modifier in disease pathogenesis.


.0021 EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2

COL1A2, IVS6DS, G-A, +1
   RCV000018791...

In a patient with Ehlers-Danlos syndrome type VIIB (EDSARTH2; 617821) reported by Minor et al. (1986), Vasan et al. (1991) identified a heterozygous G-to-A transition in the first nucleotide of intron 6 of the COL1A2 gene, resulting in the deletion of exon 6. Minor et al. (1986) found that fibroblasts from this patient synthesized shortened pro-alpha-2(I) chains. Vasan et al. (1991) pointed out that other cases of EDS7 had single base mutations causing skipping of exon 6 in either the COL1A1 or the COL1A2 gene. Lehmann et al. (1994) identified the same mutation in a Lebanese child of Arab descent.

Nicholls et al. (1991) identified this splice site mutation in a 29-year-old male with bilateral hip dislocation at birth and with other features of EDS7B. Loss of exon 6 resulted in the loss of the procollagen-N-propeptidase cleavage site and of a lysine residue that normally participates in covalent intermolecular crosslinking within collagen fibers. The patient's affected daughter was born with bilateral hip dislocation, joint hyperflexibility, feet in the equinovarus position, and hyperextensible skin, was also affected. This was 1 of the few observations of transmission of this disorder.

Watson et al. (1992) found the same mutation in a patient with EDS7B previously described by Viljoen et al. (1987). The mother and her 4 children had generalized articular laxity, joint dislocations and subluxations, and wormian bones in the skull. The authors suggested that the last feature may be more common in EDS7 than previously realized.


.0022 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, IVS33DS, G-A, +5
  
RCV000018792

In a case of lethal osteogenesis imperfecta (166210), Ganguly et al. (1991) found substitution of adenine for guanine at position +5 of the donor splice site of intron 33. One allele in the patient lacked the 54 basepairs of exon 33.


.0023 OSTEOGENESIS IMPERFECTA, TYPE IV

OSTEOGENESIS IMPERFECTA, TYPE III, INCLUDED
COL1A2, GLY586VAL
  
RCV000018793...

Bateman et al. (1991) used the chemical cleavage method for detecting mismatched bases in heteroduplexes formed between patient mRNA and control cDNA probes to demonstrate a single-base mutation in a sporadic case of type IV osteogenesis imperfecta (OI4; 166220). A G-to-U change at basepair 2162 of the COL1A2 mRNA resulted in the substitution of glycine by valine at amino acid position 586 of the helix (G586V). Disruption of the critical Gly-X-Y repeating unit resulted in helix destabilization, as evidenced by decreased thermal stability. The rapid detection of the OI mutation by the chemical cleavage method permitted application of the technique to prenatal diagnosis in the next pregnancy by chorion villus sampling.

Forlino et al. (1994) described type III OI (OI3; 259420) in a patient with a G586V substitution in the alpha-2 chain of collagen I.

Lund et al. (1997) described the same mutation, a G586V substitution, in the alpha-1 chain (COL1A1) in a case of lethal OI2 (120150.0056). 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.


.0024 MOVED TO 120160.0021


.0025 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY694ARG
  
RCV000018795

In a case of lethal osteogenesis imperfecta (166210), Tsuneyoshi et al. (1991) demonstrated substitution of arginine for glycine-694 (G694R).


.0026 OSTEOGENESIS IMPERFECTA, ATYPICAL, WITH JOINT HYPERMOBILITY

COL1A2, IVS9DS, 11-BP DEL, EX9DEL
  
RCV000018796

Nicholls et al. (1992) identified a novel mutation involving deletion of the 54 basepairs comprising exon 9 of the COL1A2 gene. The 8 affected individuals in 6 sibships of 4 generations of a family were all short and showed marked joint laxity, particularly in the hands, moderate hyperextensibility of the skin, blue sclerae, and easy bruising. Many had a history of late-onset fractures (from early adulthood) occurring spontaneously or after minor trauma. There was radiologic evidence of moderate to severe premature osteoporosis, particularly in affected females. Although no male-to-male transmission was observed, the pedigree was compatible with autosomal dominant inheritance and the mutation was demonstrated to be in heterozygous state in each of the affected persons. The deletion of exon 9 was shown to be due to an 11-bp deletion in the donor splice site of IVS9. Extending from bp 3 through bp 13 of IVS9, the deletion disrupted the normal GTAAGT 5-prime splice signal.


.0027 EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2

COL1A2, IVS5AS, G-C, -1
  
RCV000018797

In a mother and son with type VII Ehlers-Danlos syndrome (EDSARTH2; 617821), Chiodo et al. (1992) found heterozygosity for loss of the N-proteinase cleavage site in the alpha-2 chain of type I collagen due to inactivation of the 3-prime splice site of intron 5 by an AG-to-AC mutation and the activation of a cryptic AG splice acceptor site corresponding to positions +14 and +15 of exon 6. The mother, aged 30 years, had congenital dislocations of the hips and severe laxity of other joints. Her son, who was also born with dislocated hips, died suddenly at 3 months of age.


.0028 MOVED TO 120160.0021


.0029 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY580ASP
  
RCV000018798

Niyibizi et al. (1992) identified a gly580-to-asp substitution (G580D) in the COL1A2 gene in a case of lethal neonatal osteogenesis imperfecta (166210). The infant died at 6 months of age of progressive respiratory insufficiency. They demonstrated that the mutant molecules in this heterozygote represented a surprisingly high percentage of total collagen isolated from cortical bone; the ratio of mutant to normal chains in bone was 0.7/1. They suggested that in this case the tissue abnormalities resulted more from the presence of mutant protein than from an underexpression of matrix.


.0030 OSTEOPOROSIS, POSTMENOPAUSAL

COL1A2, GLY661SER
  
RCV000018799

Spotila et al. (1991) demonstrated a gly661-to-ser (G661S) mutation in the COL1A2 gene in a woman with features suggestive of postmenopausal osteoporosis (166710). Maternal isodisomy for chromosome 7 was described in a member of this family (Spotila et al., 1992). The 52-year-old proband was 7 years postmenopausal and had severe osteopenia with a compression fracture of the ninth thoracic vertebra. She had a history of 5 previous fractures, showed slightly blue sclerae, and was slightly hard of hearing. In the report by Spotila et al. (1992), the female proband who was heterozygous for the gly661-to-ser mutation was reported to be also heterozygous for variation at codon 459 of the COL1A2 gene (proline or alanine).

Nuytinck et al. (1996) found that the same mutation, G661S, in the COL1A1 gene (120150.0049) resulted in a severe form of osteogenesis imperfecta when in heterozygous state. The predominant role of mutations in the COL1A1 gene over the same mutation in the COL1A2 gene in determining clinical outcome was illustrated. Studies of the type I collagen heterotrimers in a woman with postmenopausal osteoporosis, in her 2 heterozygous sons, and in her son who was homozygous as a result of uniparental isodisomy revealed only mild overmodification, this being slightly less evident in the heterozygote than in the homozygote. On the other hand, the degree of overmodification of the collagen alpha chains was much more marked in the case of the COL1A1 mutation, correlating with phenotypic severity. The mother and the heterozygous sons had bone mineral density (BMD) values of more than 2 standard deviations below normal, whereas the BMD values were 5 standard deviations below normal in the homozygous son.


.0031 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, VAL255DEL
  
RCV000018800

In a patient with type III osteogenesis imperfecta (OI3; 259420), Molyneux et al. (1993) demonstrated deletion of the final 3 bases of exon 19 in one COL1A2 allele. In an RNase A protection analysis, cleavage of the hybrid formed between a normal COL2A1 sequence and RNA isolated from the patient indicated the presence of a mismatch. The deletion was then demonstrated by sequencing PCR-amplified DNA from the region of the mismatch. The deletion resulted in the loss of amino acid 255 (a valine) of the triple-helical region of half of the alpha-2 (I) collagen chains but did not disrupt the splicing of the heterogeneous nuclear RNA. The deletion was not present in either parent.


.0032 EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2

COL1A2, IVS5AS, G-C, -1
   RCV000018797

In a 32-year-old woman with Ehlers-Danlos syndrome type VIIB (EDSARTH2; 617821), Carr et al. (1994) identified a heterozygous G-to-C transversion in intron 5 of the COL1A2 gene, resulting in the skipping of exon 6. In contrast to previous reports, only 5, rather than all 18, amino acids encoded by exon 6 were deleted in the proband. The deleted peptide removed the amino-proteinase cleavage site, but not the nearby lysine crosslinking site in the amino-telopeptide of the alpha-2(I) chain. She was born with bilateral hip dislocation, bilateral knee subluxation, and generalized joint hypermobility, as well as bilateral inguinal hernias and an umbilical hernia. Throughout her life, she had multiple fractures of the small bones of her hands and feet following moderate trauma. An affected brother was similarly affected. The history of frequent fractures found in this family was slightly atypical for EDS7B and suggested phenotypic overlap with osteogenesis imperfecta.


.0033 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, GLY859SER
  
RCV000018802...

In a 35-year-old woman with type III osteogenesis imperfecta (OI3; 259420), Rose et al. (1994) identified a gly859-to-ser (G859S) substitution in the alpha-2 chain of type I collagen. The patient had many fractures at birth and continued to fracture periodically. At the age of 35, she was 94 cm tall, walked with the help of a cane, and had slightly blue sclerae and diminished hearing. Rose et al. (1994) identified the same mutation in another patient in whom skeletal anomalies were detected in utero at 15 weeks' gestation. X-rays at the time of birth demonstrated diminished calvarial mineralization but no wormian bones, thin cortices of all long bones, marked bowing of both femurs, recent fracture of the right humeral shaft, and narrow thoracic cage, but no acute or healing rib fractures. By age 5 years, he was not able to walk due to multiple and recurrent fractures, was well below the 5th percentile in height, and had a very large head size. These patients were heterozygous, consistent with the conclusion that most OI3 is inherited in an autosomal dominant manner. An exception is the form of OI3 in the black South African population (Beighton and Versfeld, 1985) which seems to be inherited in an autosomal recessive manner and may not be the result of mutations in the COL1A1 or COL1A2 gene (Wallis et al., 1993); see 259420.


.0034 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY502SER
  
RCV000018803...

In 3 unrelated individuals with perinatal lethal osteogenesis imperfecta (166210), Rose et al. (1994) found heterozygosity for a G-to-A transition at a CpG dinucleotide resulting in a gly502-to-ser (G502S) substitution in the alpha-2 chain of type I collagen. Steinmann (1995) remarked on how amazingly similar the x-ray appearance of the 3 cases was: poor mineralization of the calvarium, small chest, thin ribs with discontinuous beading and some fractures and calluses; some flattening of thoracic vertebrae; short, broad femurs with fractures; broad, angulated tibias; and thin, angulated fibulas with fractures.


.0035 OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A2, 9-BP DEL, NT3418
  
RCV000018804

Lund et al. (1996) defined the molecular defect in COL1A2 in a family with type IV osteogenesis imperfecta (OI4; 166220) spanning 3 generations: the grandmother, a son and daughter of hers, and a daughter of the daughter. The color of the sclerae was normal. There were no signs of dentinogenesis imperfecta and hearing was normal. The grandmother was more mildly affected than her descendants; she was 168 cm tall and was fully mobile throughout her life, whereas the daughter and granddaughter were 146 cm and 148 cm tall, respectively, and walked with crutches. Sequencing of the COL1A2 gene indicated a 9-bp deletion of nucleotides 3418 to 3426, corresponding to the deletion of codons 1003 to 1006 of the gene and 3 amino acids, gly-pro-pro, of the protein.


.0036 OSTEOGENESIS IMPERFECTA, TYPE IV, WITH DENTINOGENESIS IMPERFECTA

COL1A2, IVS21DS, G-A, +5
  
RCV000490711...

In an 8-year-old boy referred for dental assessment of dentinogenesis imperfecta, Nicholls et al. (1996) found joint hypermobility and some features of mild osteogenesis imperfecta (166220) although he had suffered few fractures. He had fractured his left tibia after a minor fall at age 5 and his right tibia after a substantial fall from a skateboard 1 year later. Subsequently he had broken bones in hands and feet after substantial falls and refractured his right tibia in a fall down 5 flights of stairs. The sclerae were pale blue. Dental examination and x-rays showed typical changes of dentinogenesis imperfecta type I. The boy was at the 25th centile for height and weight. Lumbar spine x-rays showed mild osteoporosis. Analysis of the collagens produced by both gingival and skin fibroblast cultures showed the synthesis and intracellular retention of an abnormal alpha-2(I) chain that migrated faster than normal on SDS-PAGE. The denaturation temperature of the mutant protein was some 6 degrees centigrade below normal. At 37 degrees centigrade secretion of abnormal protein was not detectable, but at a lower temperature (30 degrees centigrade) some was secreted into the medium. Cyanogen bromide peptide mapping of the intracellular protein indicated a probable deletion in the N-terminal peptide. RT-PCR amplification of mRNA coding for this peptide revealed a heterozygous deletion of the 108-bp exon 21 of COL1A2. Sequencing identified a G-to-A transition in the moderately conserved +5 position of the IVS21 5-prime consensus splice site, causing the skipping of exon 21. Hybridization with allele-specific oligonucleotides showed no other family member with this base change. Since the deletion was associated with the negative allele of a PvuII polymorphism in exon 25 of COL1A2, Nicholls et al. (1996) could demonstrate that the mutant pre-mRNA was alternatively spliced, yielding both full-length and deleted transcripts. Family genotype analysis indicated that the mutation had originated in the father's gene. The father and other members of the family lacked the mutation.


.0037 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, GLY1006ALA
  
RCV000018806

In a patient with type III osteogenesis imperfecta (OI3; 259420), Lu et al. (1995) demonstrated a G-to-C mutation at position 3287 (exon 49) that converted the GGC codon for glycine-1006 to GCC for alanine (G1006A) in the triple-helical domain of the COL1A2 gene.

Cole and Lam (1996) described the patient originally reported by Lu et al. (1995), noting that the 3-year-old boy had some unusual features, including brachydactyly, a large arachnoid cyst arising from the right Sylvian fissure, and bilateral chronic subdural hematoma that was diagnosed and treated at 4 months of age.

Faqeih et al. (2009), who restudied the patient at 15 years of age, designated the mutation as gly1096-to-ala (GLY1096ALA).


.0038 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, GLY586VAL
   RCV000018793...

In a child with osteogenesis imperfecta type III (OI3; 259420) and a substitution of glycine-586 by valine (G586V) in the triple-helical domain of the alpha-2(I) chain of type I collagen, Cole et al. (1996) found that the skeleton was severely porotic but contained lamellar bone and Haversian systems. From early childhood, structural failure of the bone resulted in the disruption of growth plates, progressive bone deformities, and severe growth retardation. Her development was prospectively recorded over 14 years. Her sclerae faded to a slightly bluish tint at 14 years of age. She had severe dentinogenesis imperfecta of her primary and secondary dentition. During the study, she did not develop basilar compression. She had mild conductive hearing loss. (The authors referred to the mutation as occurring at glycine-585 in the title, but used glycine-586 in the article. MHP.)


.0039 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, GLY751SER
  
RCV000018808...

De Paepe et al. (1997) demonstrated homozygosity for a gly751-to-ser mutation (G751S) in the COL1A2 gene in 2 sibs with type III osteogenesis imperfecta (OI3; 259420). The parents were first cousins. The heterozygous father had sustained 2 fractures after specific trauma. He was short (1.50 m), had a large head with triangular-shaped face, varus deformity and reduced mobility of the hips, and mild bowing of the lower legs. X-ray examination showed generalized osteopenia. The mother had no history of fractures, but like the father, suffered from diffuse articular pain. She was short (1.47 m) and showed generalized osteopenia on x-ray.


.0040 OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A2, IVS26DS, A-G, +3
  
RCV000622570...

Zolezzi et al. (1997) identified a splice mutation in the COL1A2 gene in a family that came to attention after ultrasonographic analysis had shown bowing and fractures of femora and tibiae in a female fetus at 25 weeks' gestation. Subtle clinical and radiologic signs of osteogenesis imperfecta (OI4; 166220), previously unrecognized, were found in the father and paternal grandmother. Linkage analysis indicated COL1A2 as the disease locus. Heteroduplex analysis of RT-PCR amplification products of COL1A2 mRNA from the proband and subsequent sequencing of the candidate region demonstrated the presence of normal transcripts and a minority of transcripts lacking exon 26 (54 bp) of COL1A2. Sequencing of PCR-amplified genomic DNA identified an A-to-G transition in the moderately conserved +3 position of the IVS26 donor splice site. Studies of dermal fibroblasts showed intracellular retention of the mutant protein. Failure to detect the shortened alpha-2 chains either in the medium or in the cell layer may have been the consequence of their instability at physiologic temperature.


.0041 COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 2

COL1A2, IVS9DS, G-A, +5
  
RCV000018810...

Nathanson et al. (1997) described a 14-year-old and his 4-generation family who had a mixed osteogenesis imperfecta Ehlers-Danlos syndrome phenotype (OIEDS2; 619120) that resulted from an exon-skipping mutation in the COL1A2 gene. The proband had short stature, hypermobility and dislocation of large and small joints, blue sclerae, soft hyperextensible skin, decreased adipose tissue, and multiple fractures. He developed subacute bacterial endocarditis on a bicuspid aortic valve, requiring valve replacement surgery. The ascending aorta showed an abrupt transition in the proximal ascending aorta from normal to an area of disruption of elastin fibers with marked medial cystic necrosis and generalized mucomyxoid changes. Other affected family members were at or below the 5th centile in height with blue sclerae, joint laxity, and/or fractures. The proband's sister had congenital dislocated hips requiring surgery. The proband had a G-to-A transition in the fifth nucleotide of intron 9 of the COL1A2 gene, which caused skipping of exon 9. The shortened collagen chain disrupted the alignment of the 3 collagen chains forming the triple helix at exon 6, the site of the N-proteinase procollagen cleavage site and lysyl crosslinking. With the malalignment at exon 6, Nathanson et al. (1997) predicted that decreased crosslinking between chains would result in decreased tensile strength and a tendency to fracture.


.0042 EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2

COL1A2, IVS5AS, A-G, -2
  
RCV000018811...

In 5 affected members of a family with Ehlers-Danlos syndrome type VIIB (EDSARTH2; 617821), Byers et al. (1997) identified a heterozygous A-to-G transition in intron 5 of the COL1A2 gene, resulting in the production of a protein lacking the first 5 amino acids encoded by exon 6, including the N-proteinase site and the pepsin-sensitive site. Affected individuals had dislocated hips, repeated dislocation of multiple joints, and joint laxity. No affected relatives had fractures, dental or hearing abnormalities, blue sclerae, poor wound healing, or hernias.


.0043 COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 2

COL1A2, 13.5-KB DUP
   RCV000018812

Raff et al. (2000) described a 13.5-kb duplication involving 20 exons in the COL1A2 gene in a patient with features of osteogenesis imperfecta and Ehlers-Danlos syndrome (OIEDS2; 619120). The patient was a 22-month-old boy seen because of a history of clubfeet and bilateral congenital hip dislocation. At 22 months, the patient had a prominent forehead with an anterior fontanel measuring 3x3 cm. His sclerae were blue-gray, and his teeth had an opalescent appearance. An umbilical hernia was present. He had generalized joint hypermobility but only mild hyperextensibility of the skin. He was neurologically normal and developmentally appropriate. At the age of 5 years, he had a normal gait but frequent dislocation of the left shoulder. His umbilical hernia was still evident and was eventually excised surgically. Generalized joint hypermobility, gray sclerae, and eroded dentition remained remarkable. At 7 years of age, he sustained a fracture of the distal tibia. At 8.5 years of age, he had an advanced bone age of 11.5 years. Bone density appeared normal. Because of the nature of trimer assembly, the additional polypeptide material (477 amino acids) was located almost entirely as an amino-terminal extension of the trimer such that triple helix integrity was largely intact. This suggested that chain association at the C-terminal end of the molecule drives any expansion of the triple helix toward the N-terminal end of the protein.


.0044 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, GLY277TRP
  
RCV000018813

In a 9-year-old Turkish boy with severely deforming osteogenesis imperfecta (OI3; 259420), Nuytinck et al. (2000) identified a G-to-T transversion at nucleotide 1238 of the COL1A2 gene, resulting in the substitution of a glycine by a tryptophan residue at position 277 (G277Y) of the alpha-2(I) collagen chain. Nuytinck et al. (2000) noted this as the first described mutation in which a glycine residue was replaced by a tryptophan residue, which they noted was the most voluminous amino acid. Nuytinck et al. (2000) considered the nonlethal phenotype associated with this mutation, unexpected in view of the huge size of the tryptophan residue, to support the regional model of phenotypic severity for COL1A2 mutations, in which the phenotype is determined primarily by the nature of the collagen domain rather than the type of the glycine substitution involved.


.0045 EHLERS-DANLOS SYNDROME, CARDIAC VALVULAR TYPE

COL1A2, IVS11DS, G-A, +5
  
RCV000018814

In a patient with Ehlers-Danlos syndrome with a cardiac valvular phenotype (EDSCV; 225320), Byers (2002) identified compound heterozygosity for 2 splice site mutations in the COL1A2 gene resulting in complete failure to make pro-alpha-2 chains. One mutation, IVS11+5G-A, inactivated the normal splice site and led to the use of a normally cryptic site and the inclusion of 60 nucleotides in the mRNA derived from this allele. The sequence contained a stop codon, TAA, and, as a result, the mRNA from this allele was very unstable and in low abundance. The second mutation, IVS24+1G-C (120160.0046), also destroyed the normal donor site and led to use of a cryptic donor site upstream in exon 24 that resulted in removal of 8 nucleotides from the mRNA, a translational frameshift, and the appearance of a premature termination codon, TGA, in the sequence provided by exon 26. Again this mRNA was extremely unstable. The effects on mRNA were thought to reflect nonsense-mediated decay (NMD).

The patient described by Byers (2002) and Schwarze et al. (2004) had suffered from frequent joint dislocations and torn tendons. He was relatively short of stature and had striking loose-jointedness. At the age of 45 years, the patient had severe mitral regurgitation and moderate aortic regurgitation with borderline dilatation of the aortic root (McKusick, 2002).

Schwarze et al. (2004) reported that, following episodes of arrhythmias and atrial fibrillation, the patient described by Byers (2002) underwent mitral and aortic valve replacement surgery. Although the procedure itself was uneventful, once the prosthetic valves were placed, first the mitral annulus (not the prosthetic valve) dehisced from the ventricle, then the aortic valve separated from the atrioventricular groove, and finally there was massive leakage through the left ventricular myocardium with disintegration of the entire left ventricle, from the which the patient died.


.0046 EHLERS-DANLOS SYNDROME, CARDIAC VALVULAR TYPE

COL1A2, IVS24DS, G-C, +1
  
RCV000018815

For discussion of the splice site mutation in the COL1A2 gene (IVS24+1G-C) that was found in compound heterozygous state in a patient with Ehlers-Danlos syndrome with a cardiac valvular phenotype (EDSCV; 225320) by Schwarze et al. (2004), see 120160.0045.


.0047 EHLERS-DANLOS SYNDROME, CARDIAC VALVULAR TYPE

COL1A2, IVS24DS, G-A, +1
  
RCV000018816...

Hata et al. (1988) described a patient with a form of Ehlers-Danlos syndrome (EDSCV; 225320) and complete absence of COL1A2 chain and their derivatives in tissues. The patient's fibroblasts contained less than 10% of the normal mRNAs for this chain, but the DNA contained a normal number of COL1A2 genes. The patient had suffered from hyperextensibility of the skin, hypermobility of the joints, especially joints of the fingers, and proneness to scar formation since childhood. At age 35 years, she noticed easy bruisability of the skin. She complained of palpitation and shortness of breath with exertion, and mitral valve regurgitation due to prolapse of the valve was present. She also displayed slightly blue sclerae. The same patient was reported by Kojima et al. (1988), who noted that she had had mitral valve replacement. In this patient, Schwarze et al. (2004) identified compound heterozygosity for 2 splice site mutations in the COL1A2 gene: IVS24+1G-A and IVS1+717A-G (120160.0048). The patient, then aged 65 years, had soft skin and no history of fractures.


.0048 EHLERS-DANLOS SYNDROME, CARDIAC VALVULAR TYPE

COL1A2, IVS1DS, A-G, +717
  
RCV000018817

For discussion of the splice site mutation in the COL1A2 gene (IVS1+717A-G) that was found in compound heterozygous state in a patient with Ehlers-Danlos syndrome with a cardiac valvular phenotype (EDSCV; 225320) by Schwarze et al. (2004), see 120160.0047.


.0049 COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 2

COL1A2, IVS46DS, T-C, +2
  
RCV000018818

Nicholls et al. (2001) presented evidence of homozygosity for a splicing defect in the COL1A2 gene in an offspring of first-cousin parents with combined osteogenesis imperfecta and Ehlers-Danlos syndrome-2 (OIEDS2; 619120). Marked ligamentous laxity and muscle hypertonia had been noted first at her premature (28 weeks' gestation) birth. Delayed ambulation was attributed to ligamentous laxity. At the age of 9 years she was of average height but showed marked generalized joint laxity, pes planus, and valgus heels leading to a secondary shortening of the Achilles tendon. Her skin was normal, her sclerae were pale blue, and there was dental overcrowding but no dentinogenesis imperfecta. There was a history of recurrent patellar dislocations and fractures of the skull, clavicle, fingers (3), and a toe following separate minimal traumas. The proband was found to be homozygous for a T-to-C transition at nucleotide +2 of the donor splice site of IVS46. The mother, who showed some joint laxity, and a sister were carriers of the mutation; the father was not available for testing. There was no evidence of exon skipping in this case; instead, the predominant product arose from use of a cryptic donor splice site using the second and third bases of a glycine codon 17 bp upstream of the normal splice junction as the obligate GT-dinucleotide. Thus, for most of the mature mRNA, the last 17 bp of exon 46 were deleted and the resultant frameshift introduced a termination codon just 3 codons downstream.


.0050 OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A2, GLY379ALA
  
RCV000018819...

In a 35-year-old woman with osteogenesis imperfecta type IV (OI4; 166220) and dentinogenesis imperfecta, which thus might be classified as OI type IVB, Johnson et al. (2002) identified a 1406G-C transversion in the COL1A2 gene, resulting in a gly379-to-ala substitution (G179A, in which the first glycine of the triple helix is referred to as the index position, or G469A when the initiator methionine is the reference point). Her phenotype was atypical in that she had persistent blue sclerae, which occurs in up to 10% of patients with OI4, and an improvement in congenital skeletal deformities. As a child, she had shortening of the limbs and severe bowing of the legs. After casting of her legs and learning to walk, however, her lower limbs showed dramatic improvement which had been maintained. Two of her children showed marked skeletal abnormalities, including femoral bowing, wormian bones, and osteopenia. The authors noted that the proband was initially thought to have kyphomelic dysplasia (211350).


.0051 EHLERS-DANLOS SYNDROME, CARDIAC VALVULAR TYPE

COL1A2, GLU1201TER
  
RCV000018820

In a 30-year-old man with autosomal recessive Ehlers-Danlos syndrome with a cardiac valvular phenotype (EDSCV; 225320), Schwarze et al. (2004) identified a homozygous 3601G-T transversion in exon 50 of the COL1A2 gene, resulting in a glu1201-to-ter (E1201X) mutation. The phenotypically normal parents were second cousins. He had a large secundum-type atrial septal defect, mitral valve prolapse with significant mitral regurgitation, and severe aortic valve regurgitation. His aortic root diameter at age 29 years was 36 mm, at the upper limit of normal. He developed marked left ventricular enlargement and had his aortic and mitral valves replaced with prosthetic valves, with no surgical complications. Perforation of the femoral artery and vein occurred in the course of preoperative diagnostic cardiac catheterization, and the cardiac surgeon described the tissues as extremely soft.

In a 24-year-old woman and her 12-year-old sister, born to apparently unrelated parents in a small town in southern Italy, with EDSCV, Guarnieri et al. (2019) identified homozygosity for the c.3601G-T transversion (c.3601G-T, NM_000089.3) in exon 50 of the COL1A2 gene, resulting in an E1201X mutation. The sisters had generalized joint hypermobility that was more severe in the extremities, severe flatfeet, minor skin changes, lower eyelid ectropion/ptosis, and hypoplastic distal interphalangeal creases. Cardiac involvement was progressive to moderate-severe mitral valve insufficiency in the older sister and mild in the younger sister. The aortic valve was normal in both patients. Their unaffected parents were heterozygous for the variant.


.0052 EHLERS-DANLOS SYNDROME, CARDIAC VALVULAR TYPE

COL1A2, 1-BP INS, 292C
  
RCV000018821

In a 6-year-old male with cardiac valvular type of Ehlers-Danlos syndrome (EDSCV; 225320), who had a clinical phenotype of the hypermobile (arthrochalasis) type of EDS, Malfait et al. (2006) found a total absence of the alpha-2 chain of type I collagen. Molecular studies demonstrated a homozygous insertion of a C (292_293insC) at codon 8 of COL1A2 exon 7. The resulting frameshift introduced a premature termination codon in the next amino acid position. Both first-cousin parents carried the same insertion in heterozygous state. Since some signs of mitral valve bulging were present already in the patient at the age of 6 years, cardiac follow-up by echocardiography was proposed for patients with complete absence of alpha-2 chains of type I collagen.


.0053 OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY421ASP
  
RCV000018822

In a patient with lethal osteogenesis imperfecta type II (OI2; 166210), Forlino et al. (1998) identified a 1671G-A transition in the paternally-derived allele of the COL2A1 gene, resulting in a gly421-to-asp (G421D) substitution. The patient and his unaffected father carried the rare R618Q variant (120160.0020), which the authors suggested was not responsible for the OI phenotype. Forlino et al. (1998) determined that the G421D variant showed dramatic delay in the alpha-2(I) electrophoretic mobility caused by a kink in the mutated collagen chains. Rotary shadowing electron microscopy of secreted fibroblast procollagen from the patient confirmed the presence of a kink in the region of the helix containing the glycine substitution.


.0054 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, GLY1090ASP
  
RCV000018823

In a 17-year-old girl with osteogenesis imperfecta type III and brachydactyly (OI3; 259420), who had a left parietal subdural hematoma with no history of preceding trauma, Faqeih et al. (2009) identified a gly1090-to-asp (G1090D) substitution in exon 49 of the COL1A2 gene.


.0055 OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, GLY1099ARG
  
RCV000018824

In a 6.8-year-old girl with osteogenesis imperfecta type III and brachydactyly (OI3; 259420), who developed an epidural hematoma after falling from her wheelchair, Faqeih et al. (2009) identified a gly1099-to-arg (G1099R) substitution in exon 49 of the COL1A2 gene.


.0056 COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 2

COL1A2, 1-BP DEL, A, 324+4
  
RCV001270302

In a female patient (P3) with combined osteogenesis imperfecta and Ehlers-Danlos syndrome-2 (OIEDS2; 619120), Malfait et al. (2013) identified a heterozygous 1-bp deletion (c.324+4delA, NM_000089.3) in the COL1A2 gene that resulted in skipping of exon 7.


.0057 COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 2

COL1A2, GLY109ASP
  
RCV000490674...

In a male patient (P4) with combined osteogenesis imperfecta and Ehlers-Danlos syndrome-2 (OIEDS2; 619120), Malfait et al. (2013) identified a heterozygous c.326G-A transition (c.326G-A, NM_00089.3) in exon 8 of the COL1A2 gene, resulting in a gly109-to-asp (G109D) substitution.


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  82. Phillips, C. L., Shrago-Howe, A. W., Pinnell, S. R., Wenstrup, R. J. A substitution at a non-glycine position in the triple-helical domain of pro-alpha-2(I) collagen chains present in an individual with a variant of the Marfan syndrome. J. Clin. Invest. 86: 1723-1728, 1990. [PubMed: 1978725, related citations] [Full Text]

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  90. Sasaki, T., Arai, K., Ono, M., Yamaguchi, T., Furuta, S., Nagai, Y. Ehlers-Danlos syndrome: a variant characterized by the deficiency of pro-alpha-2 chain of type I procollagen. Arch. Derm. 123: 76-79, 1987. [PubMed: 3800425, related citations] [Full Text]

  91. Schwarze, U., Hata, R.-I., McKusick, V. A., Shinkai, H., Hoyme, H. E., Pyeritz, R. E., Byers, P. H. Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway. Am. J. Hum. Genet. 74: 917-930, 2004. [PubMed: 15077201, images, related citations] [Full Text]

  92. Shupp Byrne, D. E., Church, R. L. Assignment of the genes for mouse type I procollagen to chromosome 16 using mouse fibroblast-Chinese hamster somatic cell hybrids. Somat. Cell Genet. 9: 313-331, 1983. [PubMed: 6857446, related citations] [Full Text]

  93. Sillence, D. O., Senn, A., Danks, D. M. Genetic heterogeneity in osteogenesis imperfecta. J. Med. Genet. 16: 101-116, 1979. [PubMed: 458828, related citations] [Full Text]

  94. Solomon, E., Hiorns, L., Dalgleish, R., Tolstoshev, P., Crystal, R., Sykes, B. Regional localization of the human alpha-2(I) collagen gene on chromosome 7 by molecular hybridization. Cytogenet. Cell Genet. 35: 64-66, 1983. [PubMed: 6825474, related citations] [Full Text]

  95. Spotila, L. D., Constantinou, C. D., Sereda, L., Ganguly, A., Riggs, B. L., Prockop, D. J. Mutation in a gene for type I procollagen (COL1A2) in a woman with postmenopausal osteoporosis: evidence for phenotypic and genotypic overlap with mild osteogenesis imperfecta. Proc. Nat. Acad. Sci. 88: 5423-5427, 1991. [PubMed: 2052622, related citations] [Full Text]

  96. Spotila, L. D., Sereda, L., Prockop, D. J. Partial isodisomy for maternal chromosome 7 and short stature in an individual with a mutation at the COL1A2 locus. Am. J. Hum. Genet. 51: 1396-1405, 1992. [PubMed: 1463018, related citations]

  97. Steinmann, B., Rao, V. H., Gitzelmann, R. A structurally abnormal alpha-2(I) collagen chain in a further patient with the Ehlers-Danlos syndrome type VII. Ann. N.Y. Acad. Sci. 460: 506-509, 1985.

  98. Steinmann, B., Tuderman, L., Peltonen, L., Martin, G. R., McKusick, V. A., Prockop, D. J. Evidence for a structural mutation of procollagen type I in a patient with the Ehlers-Danlos syndrome type VII. J. Biol. Chem. 255: 8887-8893, 1980. [PubMed: 6773953, related citations]

  99. Steinmann, B. Personal Communication. Zurich, Switzerland 2/17/1995.

  100. Superti-Furga, A., Pistone, F., Romano, C., Steinmann, B. Clinical variability of osteogenesis imperfecta linked to COL1A2 and associated with a structural defect in the type I collagen molecule. J. Med. Genet. 26: 358-362, 1989. [PubMed: 2567784, related citations] [Full Text]

  101. Tromp, G., Prockop, D. J. Single base mutation in the pro-alpha-2(I) collagen gene that causes efficient splicing of RNA from exon 27 to exon 29 and synthesis of a shortened but in-frame pro-alpha-2(I) chain. Proc. Nat. Acad. Sci. 85: 5254-5258, 1988. [PubMed: 2839839, related citations] [Full Text]

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  103. Tsukahara, M., Shinkai, H., Asagami, C., Eguchi, T., Kajii, T. A disease with features of cutis laxa and Ehlers-Danlos syndrome: report of a mother and daughter. Hum. Genet. 78: 9-12, 1988. [PubMed: 3338795, related citations] [Full Text]

  104. Tsuneyoshi, T., Westerhausen, A., Constantinou, C. D., Prockop, D. J. Substitutions for glycine alpha-1-637 and glycine alpha-2-694 of type I procollagen in lethal osteogenesis imperfecta: the conformational strain on the triple helix introduced by a glycine substitution can be transmitted along the helix. J. Biol. Chem. 266: 15608-15613, 1991. [PubMed: 1874719, related citations]

  105. Vasan, N. S., Kuivaniemi, H., Vogel, B. E., Minor, R. R., Wootton, J. A. M., Tromp, G., Weksberg, R., Prockop, D. J. A mutation in the pro-alpha-2(I) gene (COL1A2) for type I procollagen in Ehlers-Danlos syndrome type VII: evidence suggesting that skipping of exon 6 in RNA splicing may be a common cause of the phenotype. Am. J. Hum. Genet. 48: 305-317, 1991. [PubMed: 1990839, related citations]

  106. Viljoen, D., Goldblatt, J., Thompson, D., Beighton, P. Ehlers-Danlos syndrome: yet another type? Clin. Genet. 32: 196-201, 1987. [PubMed: 3621666, related citations] [Full Text]

  107. Vomund, A. N., Braddock, S. R., Krause, G. F., Phillips, C. L. Potential modifier role of the R618Q variant of pro-alpha2(I) collagen in type I collagen fibrillogenesis: in vitro assembly analysis. Molec. Genet. Metab. 82: 144-153, 2004. [PubMed: 15172002, related citations] [Full Text]

  108. Wallis, G. A., Sykes, B., Byers, P. H., Mathew, C. G., Viljoen, D., Beighton, P. Osteogenesis imperfecta type III: mutations in the type I collagen structural genes, COL1A1 and COL1A2, are not necessarily responsible. J. Med. Genet. 30: 492-496, 1993. [PubMed: 8100856, related citations] [Full Text]

  109. Wallis, G., Beighton, P., Boyd, C., Mathew, C. G. Mutations linked to the pro alpha-2(I) collagen gene are responsible for several cases of osteogenesis imperfecta type I. J. Med. Genet. 23: 411-416, 1986. [PubMed: 3023615, related citations] [Full Text]

  110. Watson, R. B., Wallis, G. A., Holmes, D. F., Viljoen, D., Byers, P. H., Kadler, K. E. Ehlers Danlos syndrome type VIIB: incomplete cleavage of abnormal type I procollagen by N-proteinase in vitro results in the formation of copolymers of collagen and partially cleaved pNcollagen that are near circular in cross-section. J. Biol. Chem. 267: 9093-9100, 1992. [PubMed: 1577745, related citations]

  111. Weil, D., Bernard, M., Combates, N., Wirtz, M. K., Hollister, D. W., Steinmann, B., Ramirez, F. Identification of a mutation that causes exon skipping during collagen pre-mRNA splicing in an Ehlers-Danlos syndrome variant. J. Biol. Chem. 263: 8561-8564, 1988. [PubMed: 2454224, related citations]

  112. Weil, D., D'Alessio, M., Ramirez, F., Eyre, D. R. Structural and functional characterization of a splicing mutation in the pro-alpha-2(I) collagen gene of an Ehlers-Danlos type VII patient. J. Biol. Chem. 265: 16007-16011, 1990. [PubMed: 2394758, related citations]

  113. Weil, D., D'Alessio, M., Ramirez, F., Steinmann, B., Wirtz, M. K., Glanville, R. W., Hollister, D. W. Temperature-dependent expression of a collagen splicing defect in the fibroblasts of a patient with Ehlers-Danlos syndrome type VII. J. Biol. Chem. 264: 16804-16809, 1989. [PubMed: 2777808, related citations]

  114. Wenstrup, R. J., Cohn, D. H., Cohen, T., Byers, P. H. Arginine for glycine substitution in the triple-helical domain of the products of one alpha-2(I) collagen allele (COL1A2) produces the osteogenesis imperfecta type IV phenotype. J. Biol. Chem. 263: 7734-7740, 1988. [PubMed: 2897363, related citations]

  115. Wenstrup, R. J., Lever, L. W., Phillips, C. L., Quarles, L. D. Mutations in the COL1A2 gene of type I collagen that result in nonlethal forms of osteogenesis imperfecta. Am. J. Med. Genet. 45: 228-232, 1993. [PubMed: 8456807, related citations] [Full Text]

  116. Wenstrup, R., Shrago, A., Phillips, C., Byers, P., Cohn, D. Osteogenesis imperfecta type IV: analysis for mutations in alpha-2(I) chains of type I collagen by alpha-2(I)-specific cDNA synthesis and polymerase chain reaction. Ann. N.Y. Acad. Sci. 580: 546-548, 1990.

  117. Willing, M. C., Cohn, D. H., Starman, B., Holbrook, K. A., Greenberg, C. R., Byers, P. H. Heterozygosity for a large deletion in the alpha-2(I) collagen gene has a dramatic effect on type I collagen secretion and produces perinatal lethal osteogenesis imperfecta. J. Biol. Chem. 263: 8398-8404, 1988. [PubMed: 3372533, related citations]

  118. Wirtz, M. K., Glanville, R. W., Steinmann, B., Rao, V. H., Hollister, D. W. Ehlers-Danlos syndrome type VIIB: deletion of 18 amino acids comprising the N-telopeptide region of a pro-alpha-2(I) chain. J. Biol. Chem. 262: 16376-16385, 1987. [PubMed: 3680255, related citations]

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  120. Zolezzi, F., Valli, M., Clementi, M., Mammi, I., Cetta, G., Pignatti, P. F., Mottes, M. Mutation producing alternative splicing of exon 26 in the COL1A2 gene causes type IV osteogenesis imperfecta with intrafamilial clinical variability. Am. J. Med. Genet. 71: 366-370, 1997. [PubMed: 9268111, related citations] [Full Text]


Sonja A. Rasmussen - updated : 09/12/2022
Sonja A. Rasmussen - updated : 12/10/2020
Marla J. F. O'Neill - updated : 04/10/2018
Nara Sobreira - updated : 4/11/2011
Marla J. F. O'Neill - updated : 8/27/2010
Joanna S. Amberger - updated : 3/16/2010
Ada Hamosh - updated : 7/9/2008
Cassandra L. Kniffin - updated : 6/18/2008
Cassandra L. Kniffin - updated : 5/17/2007
Victor A. McKusick - updated : 9/20/2006
Victor A. McKusick - updated : 4/27/2004
Cassandra L. Kniffin - updated : 11/10/2003
Victor A. McKusick - updated : 8/26/2003
Victor A. McKusick - updated : 8/2/2001
Michael J. Wright - updated : 7/20/2001
Victor A. McKusick - updated : 2/16/2000
Victor A. McKusick - updated : 3/13/1998
Victor A. McKusick - updated : 12/11/1997
Victor A. McKusick - updated : 10/24/1997
Victor A. McKusick - updated : 9/10/1997
Victor A. McKusick - updated : 6/18/1997
Victor A. McKusick - updated : 5/16/1997
Victor A. McKusick - updated : 3/21/1997
Iosif W. Lurie - updated : 9/11/1996
Creation Date:
Victor A. McKusick : 6/4/1986
carol : 09/12/2022
carol : 07/30/2021
carol : 07/29/2021
carol : 06/24/2021
carol : 12/10/2020
alopez : 11/07/2018
alopez : 06/26/2018
carol : 04/11/2018
carol : 04/10/2018
carol : 12/21/2017
carol : 12/21/2017
carol : 07/14/2016
carol : 5/3/2016
joanna : 11/5/2015
carol : 9/15/2015
mcolton : 8/17/2015
carol : 6/23/2011
carol : 4/11/2011
terry : 4/11/2011
carol : 12/23/2010
carol : 12/10/2010
carol : 12/9/2010
carol : 12/9/2010
carol : 12/3/2010
wwang : 9/1/2010
terry : 8/27/2010
carol : 3/17/2010
carol : 3/17/2010
joanna : 3/16/2010
carol : 1/21/2010
carol : 10/9/2009
joanna : 8/4/2009
joanna : 8/4/2009
terry : 1/13/2009
carol : 12/4/2008
wwang : 7/18/2008
terry : 7/9/2008
wwang : 7/7/2008
ckniffin : 6/18/2008
carol : 12/11/2007
wwang : 5/22/2007
ckniffin : 5/17/2007
ckniffin : 5/17/2007
alopez : 3/15/2007
carol : 11/27/2006
alopez : 10/13/2006
terry : 9/20/2006
wwang : 3/1/2006
alopez : 6/30/2004
alopez : 6/30/2004
tkritzer : 4/29/2004
terry : 4/27/2004
carol : 11/10/2003
carol : 11/10/2003
terry : 8/26/2003
carol : 1/10/2003
carol : 10/7/2002
tkritzer : 10/4/2002
mcapotos : 12/26/2001
carol : 11/24/2001
mcapotos : 8/15/2001
mcapotos : 8/13/2001
terry : 8/2/2001
alopez : 7/26/2001
terry : 7/20/2001
alopez : 2/28/2000
terry : 2/16/2000
dkim : 12/10/1998
dkim : 12/9/1998
terry : 6/22/1998
alopez : 5/12/1998
alopez : 3/17/1998
terry : 3/13/1998
mark : 12/20/1997
terry : 12/11/1997
terry : 10/28/1997
alopez : 10/27/1997
terry : 10/24/1997
terry : 9/16/1997
terry : 9/10/1997
joanna : 8/12/1997
mark : 7/16/1997
terry : 7/7/1997
terry : 6/23/1997
jenny : 6/23/1997
alopez : 6/21/1997
mark : 6/18/1997
alopez : 6/2/1997
mark : 5/19/1997
terry : 5/19/1997
terry : 5/16/1997
terry : 5/10/1997
jenny : 3/25/1997
jenny : 3/25/1997
terry : 3/21/1997
terry : 1/27/1997
jamie : 1/21/1997
terry : 1/14/1997
carol : 9/15/1996
carol : 9/11/1996
terry : 7/2/1996
terry : 7/2/1996
terry : 6/27/1996
mark : 3/4/1996
terry : 2/21/1996
carol : 3/19/1995
mimadm : 12/22/1994
terry : 7/28/1994
davew : 7/19/1994
jason : 7/14/1994
warfield : 4/8/1994

* 120160

COLLAGEN, TYPE I, ALPHA-2; COL1A2


Alternative titles; symbols

COLLAGEN OF SKIN, TENDON, AND BONE, ALPHA-2 CHAIN


HGNC Approved Gene Symbol: COL1A2

SNOMEDCT: 102447009, 205496008, 205497004, 254110009, 32369003, 385483009, 7134007, 720858001;  


Cytogenetic location: 7q21.3     Genomic coordinates (GRCh38): 7:94,394,895-94,431,227 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
7q21.3 {Osteoporosis, postmenopausal} 166710 Autosomal dominant 3
Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2 619120 Autosomal dominant 3
Ehlers-Danlos syndrome, arthrochalasia type, 2 617821 Autosomal dominant 3
Ehlers-Danlos syndrome, cardiac valvular type 225320 Autosomal recessive 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

Cloning and Expression

De Wet et al. (1987) isolated 60 kb of cloned DNA containing the entire COL1A2 gene and 22 kb of flanking sequences. Like the homologous avian gene, the 1,366 amino acid residues of the human prepropolypeptide chain are encoded by 52 exons. Analysis of the 5-prime and 3-prime untranslated regions conclusively established the nature of 5 polymorphic mRNA transcripts. The exons are equally distributed as follows: 6 in the N-propeptide domain, 42 in the alpha-chain region, and 4 in the C-propeptide domain. Kuivaniemi et al. (1988) characterized a full-length cDNA clone for the COL1A2 gene.

Into 1-cell mouse embryos, Khillan et al. (1986) injected a hybrid gene made from DNA 2 kb upstream from the COL1A2 gene and the bacterial gene for chloramphenicol acetyltransferase (CAT). They established a number of transgenic mouse strains and found that the promoter contained information for stage- and tissue-specific expression of the COL1A2 gene. For example, the level of CAT activity was higher in extracts of tail (a structure rich in tendon) than in any other tissue tested.


Mapping

Junien et al. (1982) assigned the gene for the alpha-2 polypeptide of collagen I to chromosome 7 by means of molecular hybridization in subclones of somatic cell hybrids, using a cDNA probe. Other chromosomes, including 17, could be excluded. Using an EcoRI fragment cloned from the COL1A2 gene in somatic cell hybrids containing an X/7 translocation, Solomon et al. (1983) concluded that the alpha-2 gene of type I collagen is in the 7pter-q22 portion of chromosome 7. By use of a cDNA probe in cells of a patient trisomic for 7q, Junien et al. (1984) narrowed the assignment to 7q21. 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. Kere et al. (1989) described the linkage relationships of the COL1A2 locus and the erythropoietin (EPO) and plasminogen activator type I (PLANH1). Moreover, the same authors used pulsed field gel electrophoresis technology to construct a 3-megabase physical map including COL1A2 and 3 anonymous DNA segments.

Shupp Byrne and Church (1983) assigned the genes for the alpha-1 and the alpha-2 chains of type I collagen to mouse chromosome 16. Munke et al. (1986) corrected the assignment of Cola-1 to mouse chromosome 11 where it formed part of an evolutionarily conserved linkage group with homologous genes on human chromosome 17. Similarly, by a combination of somatic cell hybrid analysis and genetic linkage, Irving et al. (1989) demonstrated that the Cola-2 gene is located on mouse chromosome 6 where it is linked to the MET protooncogene locus.


Molecular Genetics

Amino Acid Numbering System for COL1A2

Conventional numbering for the alpha-2(I) amino acid residues involves assigning number 1 to the first glycine of the triple-helical domain. This numbering system is used in the list of allelic variants below.

Osteogenesis Imperfecta

In a patient with osteogenesis imperfecta (OI), the son of third-cousin parents, Myers et al. (1985) found a homozygous frameshift mutation in the portion of the COL1A2 gene coding the COOH-propeptide. The type I procollagen secreted by his fibroblasts contained only pro-alpha-1(I) homotrimers, although pro-alpha-2(I) chains were found intracellularly (Deak et al., 1983). Dickson et al. (1984) used nuclease S1 mapping to demonstrate the homozygous defect in the patient's mRNA coding for the pro-alpha-2(I) COOH-propeptide and a heterozygous pattern in the asymptomatic parents. Clinically, the patient's OI was moderate in severity and, according to other reports, was accompanied by blue sclerae. This is recessive inheritance of moderate OI. The reports by Myers et al. (1985), Pope et al. (1985), and Nicholls et al. (1979, 1984) concern the same patient.

Wallis et al. (1986) concluded from linkage studies using 3 DNA polymorphisms associated with the COL1A2 gene that the defect in a 'significant proportion of cases' of osteogenesis imperfecta type I is located in that gene. They quoted others as showing that mutations in the COL1A2 gene can produce not only OI type I but also OI types II, III and IV.

Knisely et al. (1988) found a karyotypic abnormality involving the COL1A2 gene in an infant who died of complications of osteogenesis imperfecta at 22 days of age. The infant had an inversion, inv(7)(p13q22). The mother carried the same inversion. The authors suggested that damage to 1 COL1A2 gene caused by the inversion might have contributed to disease in the infant if a mutation affecting the other allele was present. Knisely et al. (1989) reported that the type I procollagen chains were completely normal in both parents of the case reported by Knisely et al. (1988), which led them to conclude that the rearrangement involving chromosome 7 had nothing to do with the mutation in the COL1A2 gene in the child.

Spotila et al. (1992) identified partial isodisomy for maternal chromosome 7 in a 30-year-old man who was 143.7 cm tall and weighed 36.6 kg. He had greatly reduced bone mineral density values (below the 2nd percentile for his age and gender at all sites measured). The sclerae were slightly blue; hearing was within normal limits. Uniparental disomy (UPD) for chromosome 7 had been reported previously in 2 unrelated probands discovered because of cystic fibrosis. The proband of Spotila et al. (1991) was identified initially during a screening of relatives of a woman with postmenopausal osteoporosis resulting from a gly661-to-ser (120160.0030) mutation of the COL1A2 gene. The woman was heterozygous for the mutation as were a cousin and 2 of her 3 sons. The third son, subsequently shown to have UPD, was apparently homozygous, although his father had only the normal allele. Like the previously reported cases of maternal disomy for chromosome 7, the proband had retarded growth and short stature. At 5 loci, of which the mother and father did not share alleles, the proband had inherited only the maternal allele. He was homozygous for all informative loci examined with the exception of 1 locus on the proximal short arm of chromosome 7. Thus, the UPD was probably the result of fertilization of a maternal gamete disomic for chromosome 7, with either a nullisomic sperm or a normal sperm followed by loss of the paternal homolog.

Pepe (1993) described an ACT trinucleotide repeat VNTR within intron 12 of the COL1A2 gene. Six alleles were detected with repeats varying from 6 to 12 times. Because of a high level of heterozygosity, the use of this polymorphism in the diagnosis of osteogenesis imperfecta by the linkage principle and in forensic applications was suggested. Furthermore, the possibility that instability of the trinucleotide repeat might lead to abnormalities such as in the unexplained collagenopathies or suspected collagenopathies was raised.

De Paepe et al. (1997) reported 2 sibs with severe, progressively deforming osteogenesis imperfecta (OI type III; 259420) and homozygosity by descent for a gly751-to-ser substitution (120160.0039) in the alpha-2(I) collagen chain due to a G-to-A transition in the COL1A2 gene. The parents, who were first cousins, and 2 elder sibs were heterozygous for the mutation and presented mild clinical manifestations of OI. Collagen studies on cultured fibroblasts from 1 of the probands showed that cells from the homozygote produced only mutant, unstable collagen I, whereas cells from the heterozygote produced both normal and mutant collagen I.

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.

Trummer et al. (2001) described a gly238-to-cys mutation in the COL1A2 gene leading to severe osteogenesis imperfecta type III (259420). This was said to be the most N-terminal cysteine substitution in the gene reported up to that time. A gly238-to-ser substitution had been observed 5 times in unrelated patients showing a highly variable expression of OI (Dalgleish, 1998).

Ehlers-Danlos Syndrome, Arthrochalasia Type, 2

From studies of type I collagen in a patient with Ehlers-Danlos syndrome type VIIB (EDSARTH2; 617821), Eyre et al. (1985) determined that 1 allele of the COL1A2 gene carried a de novo mutation (120160.0001) that results in deletion of 15 to 20 residues in the junction domain that spans the N-propeptidase cleavage site and the N-telopeptide cross-linking sequence.

Minor et al. (1986) observed one case of EDS VII in which a structural abnormality of the alpha-2 chain of type I collagen was responsible for resistance to cleavage of procollagen.

By electrophoretic studies of collagen excreted from cultured skin fibroblasts, Tsukahara et al. (1988) found an alpha-2 chain with an anomaly of small molecular size in mother and daughter. Only the daughter showed clinical abnormality: loose, wrinkled skin and other features of cutis laxa, together with fragility, bruisability, and hyperextensibility of the skin, with poor wound healing and 'cigarette paper' scars. The father and another daughter were normal clinically.

In a patient with EDS VIIB, Weil et al. (1988) identified a heterozygous mutation in the COL1A2 gene (120160.0002) that results in the skipping of exon 6 and elimination of the N-proteinase cleavage site necessary for proper collagen processing.

In a patient with EDS VIIB, Weil et al. (1989) identified a de novo heterozygous mutation in the COL1A2 gene (120160.0003) that deletes the cleavage site necessary for collagen processing.

In a patient with EDS VIIB, Nicholls et al. (1991) identified a heterozygous mutation in the COL1A2 gene (120160.0021).

In affected members of 6 unrelated families with EDSARTH2, Byers et al. (1997) identified heterozygosity for mutations in the COL1A2 gene (see, e.g., 120160.0042).

Ehlers-Danlos Syndrome, Cardiac Valvular Type

Sasaki et al. (1987) described a form of EDS with deficiency of pro-alpha-2 chains of type I procollagen. The patient was a 30-year-old man known to have had aortic regurgitation for 3 years. Since infancy he had suffered from hypermobility of the joints, hyperextensibility of the skin, and prolongation of wound healing. Aortic valve replacement was performed. Histologically, the aortic valve showed abundant alcian blue-positive myxomatous matrix accompanied by scattered mesenchymal cells instead of normal collagen fibers with fibroblasts. Similar but less conspicuous changes were found in the aorta itself. A biopsy specimen of the skin showed thin, somewhat fragmentary collagen fibers, while elastic fibers appeared normal. Analysis of collagen produced by cultured fibroblasts showed a lack of detectable pro-alpha-2 chains of type I procollagen. The intracellular degradation rate of newly synthesized collagen was higher than that of normal cells, resulting in the reduction of net collagen production.

Schwarze et al. (2004) described 3 unrelated patients with a rare, recessively inherited form of EDS characterized by joint hypermobility, skin hyperextensibility, and cardiac valvular defects (EDSCV; 225320); in 2 of them, one of whom had previously been reported by Hata et al. (1988) and Kojima et al. (1988), COL1A2 mRNA instability resulted from compound heterozygosity for splice site mutations in the COL1A2 gene (120160.0045-120160.0046 and 120160.0047-120160.0048, respectively), and, in the third, it resulted from homozygosity for a nonsense mutation (E1201X; 120160.0051). The splice site mutations led to use of cryptic splice donor sites, creation of a downstream premature termination codon, and highly unstable mRNA. In the wildtype allele, the 2 introns in which these mutations occurred, IVS11 and IVS24, were usually spliced slowly in relation to their respective immediate upstream introns. In the mutant alleles, the upstream intron was removed, so that exon skipping could not occur. In the context of the mutation in IVS24, computer-generated folding of a short stretch of mRNA surrounding the mutation site demonstrated realignment of the relationships between the donor and acceptor sites that could facilitate use of a cryptic donor site. The findings suggested that the order of intron removal is an important variable in prediction of the outcome of mutation at splice sites and that folding of the nascent mRNA could be 1 element that contributes to determination of order of splicing. The complete absence of pro-alpha-2(I) chains had the effect of producing cardiac valvular disease without bone involvement.

Byers (2002) observed compound heterozygosity for 2 donor splice site mutations in the COL1A2 gene that resulted in failure to produce pro-alpha-2 chains of type I collagen (120160.0045, 120160.0046). At the age of 45 years, the patient had significant aortic and mitral valvular disease and had borderline dilatation of the root of the aorta.

In 2 sisters, born to apparently unrelated parents in a small town in southern Italy, with EDSCV, Guarnieri et al. (2019) identified homozygosity for the nonsense mutation in the COL1A2 gene (120160.0051) that was previously identified by Schwarze et al. (2004). The mutation, which was found by screening the coding regions of 20 genes involved in EDS, was present in heterozygous state in the parents. The variant was not found in large population databases.

Combined Osteogenesis Imperfecta and Ehlers-Danlos Syndrome 2

Nathanson et al. (1997) described a family with combined osteogenesis imperfecta and Ehlers-Danlos syndrome-2 (OIEDS2; 619120) due to a splice site mutation in the COL1A2 gene (120160.0041). Byers (2002) hypothesized that the phenotypic outcome from failure to incorporate pro-alpha-2 chains into type I procollagen molecules may be explained by a small amount of abnormal pro-alpha-2 chains made in the cases with OI that gets incorporated into molecules and alters mineralization.

Multiexon duplication or deletion in type I collagen genes has rarely been rarely observed and generally results in a severe or lethal phenotype. In a patient with OIEDS2, Raff et al. (2000) identified a heterozygous 13.5-kb duplication involving 20 exons in the COL1A2 gene (120160.0043), resulting in an additional 477 amino acids in the triple-helical domain. The abnormal molecule was synthesized and secreted by cultured dermal fibroblasts in a normal fashion. Electron microscopy of dermal tissue revealed small but otherwise near-normal collagen fibrils. The gene duplication occurred by mitotic sister chromatid exchange in the mother, who was mosaic for the duplication allele. Examination of the abnormal sequence suggested a means by which the duplicated molecule could be processed and properly incorporated into mature collagen fibrils.

Nicholls et al. (2001) described a 9-year-old girl, born of consanguineous parents, who was homozygous for a splice site mutation in the COL1A2 gene (120160.0049) that yielded a nonfunctional alpha-2 procollagen chain and an OIEDS clinical phenotype. The mother, who showed some joint laxity, and a younger sister were carriers of the mutation; the father was not available for testing.

Malfait et al. (2013) sequenced the COL1A1 and COL1A2 genes in 7 patients with OIEDS1 (619115) or OIEDS2 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; of the 5 mutations in COL1A2, 3 were exon skipping (see, e.g., 120160.0056) and 2 were missense (see, e.g., 120160.0057). The mutations affected the rate of type I collagen N-propeptide cleavage and disturbed normal collagen fibrillogenesis.

Reviews

Kuivaniemi et al. (1997) tabulated all reported mutations of the COL1A2 gene as well as those of 6 other collagen genes.

Dalgleish (1997) described a mutation database for the COL1A1 and COL1A2 genes accessible on the World Wide Web. See also Dalgleish (1998).


Genotype/Phenotype Correlations

Superti-Furga et al. (1989) reported a family in which osteogenesis imperfecta linked to COL1A2 and associated with a structural defect in the triple-helical region of the alpha-2 chains resulted in a very mild clinical picture in some individuals in whom the diagnosis of OI had not been made, mainly because of the lack of fractures, and severe OI in others. All affected members showed dentinogenesis imperfecta and myopia. The findings confirmed that mutations in the triple-helical region of the alpha-2 chains produce a milder phenotype than do corresponding mutations in the alpha-1 chains, but indicated that, in addition to defects in the type I collagen molecule, other factors must modulate the degree of bone involvement. In 4 out of 60 persons with deforming (nonlethal) varieties of osteogenesis imperfecta, Cohn and Byers (1991) demonstrated alpha-2 chains with a cysteine residue in the triple helix, a domain from which it is normally excluded. The clinical differences among these 4 individuals and the heterogeneity in the locations of the cysteine residues suggested that the position of the substitution within the chain is important in determining the clinical phenotype.

Malfait et al. (2006) found 8 reports of complete deficiency of the alpha-2 chains of type I collagen due to homozygosity or compound heterozygosity for a nonfunctional COL1A2 gene; see reports by Deak et al. (1983), Hata et al. (1988), Nicholls et al. (1979), Nicholls et al. (1984), Nicholls et al. (2001), Pihlajaniemi et al. (1984), Sasaki et al. (1987), and Schwarze et al. (2004). The clinical features of these patients, however, were strikingly variable, ranging from severe osteogenesis imperfecta to a mild EDS/OI-like phenotype, and associated in some adult patients with severe cardiac valvular abnormalities (EDSCV; 225320), necessitating cardiac surgery. Malfait et al. (2006) recorded the clinical features of a 6-year-old boy in whom complete lack of alpha-2 chains of type I collagen (see 120160.0052) was associated with a phenotype reminiscent of mild hypermobility EDS (130020). Careful cardiac follow-up with ultrasonography was highly recommended because of the risk for cardiac valvular problems developing in adulthood. The 6-year-old subject reported by Malfait et al. (2006) already showed abnormal mitral valve bulging. Malfait et al. (2006) suggested a possible mechanism for the variable phenotype in patients with complete deficiency of the alpha-2 chain. In most cases, the underlying COL1A2 mutations result in nonsense-mediated RNA decay (NMD) and a loss-of-function effect. The phenotypic consequences are those of a form of EDS characterized by hypermobility in childhood and complicated by cardiac valve disease in adulthood. On the other hand, COL1A2 mutations that do not result in NMD produce a gain-of-function effect with the production of abnormal collagen type I chains that disturb interaction with the normal collagen chains and lead to a severe OI phenotype.

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.

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 0, 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.

Faqeih et al. (2009) reported 3 unrelated patients with OI type III, brachydactyly, and intracranial hemorrhage, 1 of whom was previously described by Cole and Lam (1996), who all had glycine mutations involving exon 49, in the most C-terminal part of the triple-helical domain of COL1A2 (120160.0037, 120160.0054, and 120160.0055, respectively). Faqeih et al. (2009) suggested that mutations in this region of COL1A2 carry a high risk of abnormal limb development and intracranial bleeding.

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 sclerae, 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 amino-terminal end of the collagen type I triple helix had blue sclerae 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 sclerae, respectively.


ALLELIC VARIANTS 57 Selected Examples):

.0001   EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2

COL1A2, EX6DEL
ClinVar: RCV000018772

From studies of type I collagen in a patient with Ehlers-Danlos syndrome type VIIB (EDSARTH2; 617821), Eyre et al. (1985) determined that 1 allele of the COL1A2 gene carried a de novo mutation that resulted in deletion of 15 to 20 residues in the junction domain that spans the N-propeptidase cleavage site and the N-telopeptide cross-linking sequence.


.0002   EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2

COL1A2, IVS6DS, T-C, +2
SNP: rs72656357, ClinVar: RCV000018773, RCV002228037

In a Libyan patient with Ehlers-Danlos syndrome type VIIB (EDSARTH2; 617821) reported by Steinmann et al. (1985) and Wirtz et al. (1987), Weil et al. (1988) identified a heterozygous T-to-C transition in at the splice donor site of intron 6 of the COL1A2 gene, resulting in the skipping of exon 6. In this patient, Wirtz et al. (1987) had identified a deletion of 18 amino acids of the N-telopeptide of the pro-alpha-2 chain of type I collagen.

Ho et al. (1994) observed the same mutation in a Chinese patient with EDS VIIB.


.0003   EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2

COL1A2, IVS6DS, G-A, -1
SNP: rs72656356, ClinVar: RCV000018774, RCV002231016

In a patient with Ehlers-Danlos syndrome type VIIB (EDSARTH2; 617821) previously reported by Lichtenstein et al. (1973) and Steinmann et al. (1980), Weil et al. (1989) identified a de novo heterozygous G-to-A transition in the last nucleotide of exon 6 of the COL1A2 gene, resulting in the skipping of exon 6 and deletion of the cleavage site necessary for proper collagen processing. The expression of the alternative splicing in this patient was found to be temperature-dependent; cellular studies showed that missplicing was effectively abolished at 31 degrees C and gradually increased to 100% at 39 degrees C. In contrast, in the patient who had a substitution in the obligatory GT dinucleotide of the 5-prime splice site of intron 6 of COL1A2 (120160.0002), complete outsplicing of exon 6 sequences was found at all temperatures. This mutation is identical to that found in COL1A1 (120150.0026).


.0004   OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A2, GLY1012ARG
SNP: rs72659319, ClinVar: RCV000018775, RCV000321212

In a patient with osteogenesis imperfecta of Sillence type IV (166220), Wenstrup et al. (1988) found an arginine for glycine substitution at position 1012 (G1012R), the last triple-helical glycine. Increased posttranslational modification along the entire triple-helical domain resulted.


.0005   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, EX1, FS
SNP: rs72659345, ClinVar: RCV000018776

In a patient with osteogenesis imperfecta of Sillence type III (259420), Pihlajaniemi et al. (1984) demonstrated a 4-nucleotide frameshift deletion in exon 1 which instigated the use of a new termination codon 4 nucleotides 3-prime to the original site.


.0006   OSTEOGENESIS IMPERFECTA, MILD

COL1A2, EX11DEL
SNP: rs74315146, ClinVar: RCV000018777, RCV002468973, RCV003764608

In a boy with 'atypical' OI and his asymptomatic mother, Kuivaniemi et al. (1988) found deletion of 19 bp at the junction of IVS 10 and exon 11 causing abnormal splicing between exons 10 and 12 and a shortened pro-alpha-2 chain of type I collagen.


.0007   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, DEL 7EX, CODONS 586-765
ClinVar: RCV000018778

Willing et al. (1988) characterized a de novo 4.5-kb deletion in the paternally derived COL1A2 allele found in a patient with perinatal lethal osteogenesis imperfecta (166210). The intron-to-intron deletion removed the 7 exons that encode residues 586-765 of the triple-helical domain of the chain. A block in secretion appeared to result from improper assembly of the triple helix. The lethal effect may have been due in part to decreased secretion of normal collagen and secretion of a small amount of abnormal collagen that disrupts matrix formation.


.0008   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY907ASP
SNP: rs121912900, ClinVar: RCV000018779, RCV002281710

In an infant with a lethal variety of osteogenesis imperfecta (166210), Baldwin et al. (1989) found a G-to-A change that converted glycine-907 to aspartic acid (G907D). The change resulted in decreased thermal stability of type I collagen synthesized by the patient's fibroblasts.


.0009   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, EX33DEL
SNP: rs2115924259, ClinVar: RCV000018780

In a lethal form of osteogenesis imperfecta (166210), Baldwin et al. (1988) found deletion of 54 bp corresponding to exon 33.


.0010   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY547ASP
SNP: rs121912901, ClinVar: RCV000018781

By RNA sequence analysis, Bonadio et al. (1988) demonstrated heterozygosity for a glycine-to-aspartic acid substitution at position 547 (G547D) in a case of perinatal lethal osteogenesis imperfecta (166210).


.0011   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY865SER
SNP: rs121912902, ClinVar: RCV000018782

Using the Cotton chemical cleavage method to localize and characterize single bp mRNA mutations, Lamande et al. (1989) demonstrated substitution of serine for glycine at position 865 (G865S).


.0012   MOVED TO 120160.0020


.0013   OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A2, GLY646CYS
SNP: rs121912903, ClinVar: RCV000018783

Wenstrup et al. (1990) found a substitution of cystine for glycine-646 (G646C) in a family with mild osteogenesis imperfecta. Wenstrup et al. (1993) described the mutation in 2 families with type IV osteogenesis imperfecta (OI4; 166220).


.0014   OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A2, EX26DEL
ClinVar: RCV000018784

In a family with mild osteogenesis imperfecta (166220), Wenstrup et al. (1990) found that alpha-2(I) mRNA was shortened by the 54 bp coded by exon 26.


.0015   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY976ASP
ClinVar: RCV000018785

Byers (1990) provided information on this mutation.


.0016   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY805ASP
SNP: rs121912904, ClinVar: RCV000018786

Byers (1990) provided information on this mutation.


.0017   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, GLY259CYS
SNP: rs121912905, ClinVar: RCV000018787

Byers (1990) provided information on this mutation as a cause of osteogenesis imperfecta type II (166210). Wenstrup et al. (1993) reported this mutation in a single family. The phenotype was said to be 'moderately severe' or 'severe deforming,' suggesting that this may be osteogenesis imperfecta type III (OI3; 259420).


.0018   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, EX28DEL
SNP: rs1799871, ClinVar: RCV000018788

In a case of type II osteogenesis imperfecta (OI2; 166210), Tromp and Prockop (1988) found that the previously demonstrated shortened pro-alpha-2 chain of type I collagen resulted from deletion of exon 28 which in turn resulted from substitution of G for A at the 3-prime end of intron 27.


.0019   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY472CYS
SNP: rs121912906, ClinVar: RCV000018789

Edwards et al. (1990) demonstrated somatic mosaicism for this mutation in the father of 2 children with lethal osteogenesis imperfecta (OI2; 166210), each from a different partner. The mutation was found in 33% of sperm, 67% of lymphocytes, and 100% of dermal fibroblasts. The authors hypothesized that the mutation occurred very early in development in a cell that gave rise to both ectodermal and mesodermal cell lineages. Edwards et al. (1992) stated that despite the high level of mosaicism detected in somatic tissues, the only phenotypic manifestation of OI in the proband (the father) was that he was shorter than his unaffected male relatives and had mild dentinogenesis imperfecta. Thermal stability of type I collagen molecules containing the substitution was decreased but to a lesser extent than that for a nonlethal gly259-to-cys (G259C) substitution of the alpha-2(I) (120160.0017) chain, indicating that this measure of molecular stability may be of limited use in explaining the pathogenesis of OI. Edwards et al. (1992) stated that this was the second family in which recurrence of lethal OI had resulted from parental germline mosaicism for a dominant lethal mutation and the fourth family in which there was molecular evidence of parental mosaicism for a mutation that produced lethal OI. The mosaic parent in all 4 families was also mosaic for the mutation in somatic tissues. Since the mutation was detected in blood from all 4 mosaic individuals but not in DNA from cultured fibroblasts in one, blood may be the best parental somatic tissue to examine for mutation found in a sporadic affected infant.


.0020   RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

COL1A2, ARG618GLN
SNP: rs72658163, gnomAD: rs72658163, ClinVar: RCV000018790, RCV000413739, RCV000680486, RCV001162670, RCV001162671, RCV001200183, RCV001330774, RCV002228038, RCV002415422

This variant, formerly titled MARFAN SYNDROME, ATYPICAL or MARFAN SYNDROME VARIANT, has been reclassified based on the findings of Forlino et al. (1998) and Vomund et al. (2004).

Byers et al. (1981) found 2 species of the alpha-2 chain of type I collagen in 1 of 11 Marfan patients studied; one of the alpha-2 chains was normal whereas the other contained a 20-amino acid insertion in the amino-terminal propeptide. This alteration in chain size probably accounted for the 5- to 10-fold increase in collagen extraction into nondenaturing solvents from this patient's skin compared to controls. The patient of Byers et al. (1981) was a 39-year-old woman who had unaffected parents and 2 unaffected sibs. Features were equinovarus deformities of both feet at birth; arachnodactyly first noted at age 9 and lumbar scoliosis and heart murmur first noted at age 10. Aortic and mitral regurgitation with dilated root of the aorta prompted surgical replacement of the aortic valve and a portion of the ascending aorta at age 37. Her height was 164.5 cm, span 178 cm, upper segment to lower segment ratio 0.80. No lens dislocation was detected. She showed bluish-gray sclerae and mild myopia. Mild pectus carinatum was present, as well as long slender limbs with increased mobility in all joints except the fourth and fifth fingers which bilaterally showed marked camptodactyly. Henke et al. (1985) suggested that there was a 38-basepair insertion in the COL1A2 gene that caused the Marfan syndrome. Dalgleish et al. (1986) found, however, that this is a common polymorphism of the COL1A2 gene. Among 28 normal persons, 12 were homozygous for the large oligo, 12 were heterozygous, and 4 were homozygous for the small oligo. Phillips et al. (1990) further studied the patient and demonstrated a single base change, resulting in substitution of arginine-618 by glutamine at the Y position of a Gly-X-Y repeat. Family studies indicated that the substitution was inherited from the patient's father who also produced abnormally migrating pro-alpha-2(I) collagen chains and shared some of the abnormal skeletal features. The single base change at nucleotide 2258 resulted in a new Bsu36I (SauI, MstII) restriction site detectable in genomic DNA by Southern blot analysis when probed with a COL1A2 fragment. Analyses of 103 chromosomes in 52 controlled individuals were negative for the new site, indicating that the substitution is not a common polymorphism.

Forlino et al. (1998) identified the R618Q variant and a gly421-to-asp mutation (G421D; 120160.0053) in cis in a patient with lethal osteogenesis imperfecta (166210). The patient's unaffected father also carried the R618Q variant. Forlino et al. (1998) determined that the R618Q variant resulted in only mild electrophoretic delay. They suggested that G421D was the causative mutation and that R618Q is a rare variant.

Vomund et al. (2004) analyzed the helical stability and fibrillar assembly of type I collagen from cultured dermal fibroblasts of controls and 2 unrelated individuals heterozygous for the R618Q variant. They found that the thermal stability of the R618Q-containing collagen molecules did not differ statistically from control molecules, but that the diameter of assembled R618Q-containing collagen fibrils was approximately 20% of control collagen fibrils. Vomund et al. (2004) suggested that while the R618Q variant does not impact triple-helical stability, it does impact collagen fibril assembly and may therefore have a role as a modifier in disease pathogenesis.


.0021   EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2

COL1A2, IVS6DS, G-A, +1
ClinVar: RCV000018791, RCV002276560

In a patient with Ehlers-Danlos syndrome type VIIB (EDSARTH2; 617821) reported by Minor et al. (1986), Vasan et al. (1991) identified a heterozygous G-to-A transition in the first nucleotide of intron 6 of the COL1A2 gene, resulting in the deletion of exon 6. Minor et al. (1986) found that fibroblasts from this patient synthesized shortened pro-alpha-2(I) chains. Vasan et al. (1991) pointed out that other cases of EDS7 had single base mutations causing skipping of exon 6 in either the COL1A1 or the COL1A2 gene. Lehmann et al. (1994) identified the same mutation in a Lebanese child of Arab descent.

Nicholls et al. (1991) identified this splice site mutation in a 29-year-old male with bilateral hip dislocation at birth and with other features of EDS7B. Loss of exon 6 resulted in the loss of the procollagen-N-propeptidase cleavage site and of a lysine residue that normally participates in covalent intermolecular crosslinking within collagen fibers. The patient's affected daughter was born with bilateral hip dislocation, joint hyperflexibility, feet in the equinovarus position, and hyperextensible skin, was also affected. This was 1 of the few observations of transmission of this disorder.

Watson et al. (1992) found the same mutation in a patient with EDS7B previously described by Viljoen et al. (1987). The mother and her 4 children had generalized articular laxity, joint dislocations and subluxations, and wormian bones in the skull. The authors suggested that the last feature may be more common in EDS7 than previously realized.


.0022   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, IVS33DS, G-A, +5
SNP: rs72658157, ClinVar: RCV000018792

In a case of lethal osteogenesis imperfecta (166210), Ganguly et al. (1991) found substitution of adenine for guanine at position +5 of the donor splice site of intron 33. One allele in the patient lacked the 54 basepairs of exon 33.


.0023   OSTEOGENESIS IMPERFECTA, TYPE IV

OSTEOGENESIS IMPERFECTA, TYPE III, INCLUDED
COL1A2, GLY586VAL
SNP: rs121912907, ClinVar: RCV000018793, RCV000018794

Bateman et al. (1991) used the chemical cleavage method for detecting mismatched bases in heteroduplexes formed between patient mRNA and control cDNA probes to demonstrate a single-base mutation in a sporadic case of type IV osteogenesis imperfecta (OI4; 166220). A G-to-U change at basepair 2162 of the COL1A2 mRNA resulted in the substitution of glycine by valine at amino acid position 586 of the helix (G586V). Disruption of the critical Gly-X-Y repeating unit resulted in helix destabilization, as evidenced by decreased thermal stability. The rapid detection of the OI mutation by the chemical cleavage method permitted application of the technique to prenatal diagnosis in the next pregnancy by chorion villus sampling.

Forlino et al. (1994) described type III OI (OI3; 259420) in a patient with a G586V substitution in the alpha-2 chain of collagen I.

Lund et al. (1997) described the same mutation, a G586V substitution, in the alpha-1 chain (COL1A1) in a case of lethal OI2 (120150.0056). 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.


.0024   MOVED TO 120160.0021


.0025   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY694ARG
SNP: rs121912908, ClinVar: RCV000018795

In a case of lethal osteogenesis imperfecta (166210), Tsuneyoshi et al. (1991) demonstrated substitution of arginine for glycine-694 (G694R).


.0026   OSTEOGENESIS IMPERFECTA, ATYPICAL, WITH JOINT HYPERMOBILITY

COL1A2, IVS9DS, 11-BP DEL, EX9DEL
SNP: rs72656362, ClinVar: RCV000018796

Nicholls et al. (1992) identified a novel mutation involving deletion of the 54 basepairs comprising exon 9 of the COL1A2 gene. The 8 affected individuals in 6 sibships of 4 generations of a family were all short and showed marked joint laxity, particularly in the hands, moderate hyperextensibility of the skin, blue sclerae, and easy bruising. Many had a history of late-onset fractures (from early adulthood) occurring spontaneously or after minor trauma. There was radiologic evidence of moderate to severe premature osteoporosis, particularly in affected females. Although no male-to-male transmission was observed, the pedigree was compatible with autosomal dominant inheritance and the mutation was demonstrated to be in heterozygous state in each of the affected persons. The deletion of exon 9 was shown to be due to an 11-bp deletion in the donor splice site of IVS9. Extending from bp 3 through bp 13 of IVS9, the deletion disrupted the normal GTAAGT 5-prime splice signal.


.0027   EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2

COL1A2, IVS5AS, G-C, -1
SNP: rs66820119, ClinVar: RCV000018797

In a mother and son with type VII Ehlers-Danlos syndrome (EDSARTH2; 617821), Chiodo et al. (1992) found heterozygosity for loss of the N-proteinase cleavage site in the alpha-2 chain of type I collagen due to inactivation of the 3-prime splice site of intron 5 by an AG-to-AC mutation and the activation of a cryptic AG splice acceptor site corresponding to positions +14 and +15 of exon 6. The mother, aged 30 years, had congenital dislocations of the hips and severe laxity of other joints. Her son, who was also born with dislocated hips, died suddenly at 3 months of age.


.0028   MOVED TO 120160.0021


.0029   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY580ASP
SNP: rs121912909, ClinVar: RCV000018798

Niyibizi et al. (1992) identified a gly580-to-asp substitution (G580D) in the COL1A2 gene in a case of lethal neonatal osteogenesis imperfecta (166210). The infant died at 6 months of age of progressive respiratory insufficiency. They demonstrated that the mutant molecules in this heterozygote represented a surprisingly high percentage of total collagen isolated from cortical bone; the ratio of mutant to normal chains in bone was 0.7/1. They suggested that in this case the tissue abnormalities resulted more from the presence of mutant protein than from an underexpression of matrix.


.0030   OSTEOPOROSIS, POSTMENOPAUSAL

COL1A2, GLY661SER
SNP: rs72658152, ClinVar: RCV000018799

Spotila et al. (1991) demonstrated a gly661-to-ser (G661S) mutation in the COL1A2 gene in a woman with features suggestive of postmenopausal osteoporosis (166710). Maternal isodisomy for chromosome 7 was described in a member of this family (Spotila et al., 1992). The 52-year-old proband was 7 years postmenopausal and had severe osteopenia with a compression fracture of the ninth thoracic vertebra. She had a history of 5 previous fractures, showed slightly blue sclerae, and was slightly hard of hearing. In the report by Spotila et al. (1992), the female proband who was heterozygous for the gly661-to-ser mutation was reported to be also heterozygous for variation at codon 459 of the COL1A2 gene (proline or alanine).

Nuytinck et al. (1996) found that the same mutation, G661S, in the COL1A1 gene (120150.0049) resulted in a severe form of osteogenesis imperfecta when in heterozygous state. The predominant role of mutations in the COL1A1 gene over the same mutation in the COL1A2 gene in determining clinical outcome was illustrated. Studies of the type I collagen heterotrimers in a woman with postmenopausal osteoporosis, in her 2 heterozygous sons, and in her son who was homozygous as a result of uniparental isodisomy revealed only mild overmodification, this being slightly less evident in the heterozygote than in the homozygote. On the other hand, the degree of overmodification of the collagen alpha chains was much more marked in the case of the COL1A1 mutation, correlating with phenotypic severity. The mother and the heterozygous sons had bone mineral density (BMD) values of more than 2 standard deviations below normal, whereas the BMD values were 5 standard deviations below normal in the homozygous son.


.0031   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, VAL255DEL
SNP: rs869254878, ClinVar: RCV000018800

In a patient with type III osteogenesis imperfecta (OI3; 259420), Molyneux et al. (1993) demonstrated deletion of the final 3 bases of exon 19 in one COL1A2 allele. In an RNase A protection analysis, cleavage of the hybrid formed between a normal COL2A1 sequence and RNA isolated from the patient indicated the presence of a mismatch. The deletion was then demonstrated by sequencing PCR-amplified DNA from the region of the mismatch. The deletion resulted in the loss of amino acid 255 (a valine) of the triple-helical region of half of the alpha-2 (I) collagen chains but did not disrupt the splicing of the heterogeneous nuclear RNA. The deletion was not present in either parent.


.0032   EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2

COL1A2, IVS5AS, G-C, -1
ClinVar: RCV000018797

In a 32-year-old woman with Ehlers-Danlos syndrome type VIIB (EDSARTH2; 617821), Carr et al. (1994) identified a heterozygous G-to-C transversion in intron 5 of the COL1A2 gene, resulting in the skipping of exon 6. In contrast to previous reports, only 5, rather than all 18, amino acids encoded by exon 6 were deleted in the proband. The deleted peptide removed the amino-proteinase cleavage site, but not the nearby lysine crosslinking site in the amino-telopeptide of the alpha-2(I) chain. She was born with bilateral hip dislocation, bilateral knee subluxation, and generalized joint hypermobility, as well as bilateral inguinal hernias and an umbilical hernia. Throughout her life, she had multiple fractures of the small bones of her hands and feet following moderate trauma. An affected brother was similarly affected. The history of frequent fractures found in this family was slightly atypical for EDS7B and suggested phenotypic overlap with osteogenesis imperfecta.


.0033   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, GLY859SER
SNP: rs72658200, ClinVar: RCV000018802, RCV003226163

In a 35-year-old woman with type III osteogenesis imperfecta (OI3; 259420), Rose et al. (1994) identified a gly859-to-ser (G859S) substitution in the alpha-2 chain of type I collagen. The patient had many fractures at birth and continued to fracture periodically. At the age of 35, she was 94 cm tall, walked with the help of a cane, and had slightly blue sclerae and diminished hearing. Rose et al. (1994) identified the same mutation in another patient in whom skeletal anomalies were detected in utero at 15 weeks' gestation. X-rays at the time of birth demonstrated diminished calvarial mineralization but no wormian bones, thin cortices of all long bones, marked bowing of both femurs, recent fracture of the right humeral shaft, and narrow thoracic cage, but no acute or healing rib fractures. By age 5 years, he was not able to walk due to multiple and recurrent fractures, was well below the 5th percentile in height, and had a very large head size. These patients were heterozygous, consistent with the conclusion that most OI3 is inherited in an autosomal dominant manner. An exception is the form of OI3 in the black South African population (Beighton and Versfeld, 1985) which seems to be inherited in an autosomal recessive manner and may not be the result of mutations in the COL1A1 or COL1A2 gene (Wallis et al., 1993); see 259420.


.0034   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY502SER
SNP: rs121912910, ClinVar: RCV000018803, RCV002513109

In 3 unrelated individuals with perinatal lethal osteogenesis imperfecta (166210), Rose et al. (1994) found heterozygosity for a G-to-A transition at a CpG dinucleotide resulting in a gly502-to-ser (G502S) substitution in the alpha-2 chain of type I collagen. Steinmann (1995) remarked on how amazingly similar the x-ray appearance of the 3 cases was: poor mineralization of the calvarium, small chest, thin ribs with discontinuous beading and some fractures and calluses; some flattening of thoracic vertebrae; short, broad femurs with fractures; broad, angulated tibias; and thin, angulated fibulas with fractures.


.0035   OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A2, 9-BP DEL, NT3418
SNP: rs74315103, ClinVar: RCV000018804

Lund et al. (1996) defined the molecular defect in COL1A2 in a family with type IV osteogenesis imperfecta (OI4; 166220) spanning 3 generations: the grandmother, a son and daughter of hers, and a daughter of the daughter. The color of the sclerae was normal. There were no signs of dentinogenesis imperfecta and hearing was normal. The grandmother was more mildly affected than her descendants; she was 168 cm tall and was fully mobile throughout her life, whereas the daughter and granddaughter were 146 cm and 148 cm tall, respectively, and walked with crutches. Sequencing of the COL1A2 gene indicated a 9-bp deletion of nucleotides 3418 to 3426, corresponding to the deletion of codons 1003 to 1006 of the gene and 3 amino acids, gly-pro-pro, of the protein.


.0036   OSTEOGENESIS IMPERFECTA, TYPE IV, WITH DENTINOGENESIS IMPERFECTA

COL1A2, IVS21DS, G-A, +5
SNP: rs68132885, ClinVar: RCV000490711, RCV000598859, RCV002227169, RCV003766737

In an 8-year-old boy referred for dental assessment of dentinogenesis imperfecta, Nicholls et al. (1996) found joint hypermobility and some features of mild osteogenesis imperfecta (166220) although he had suffered few fractures. He had fractured his left tibia after a minor fall at age 5 and his right tibia after a substantial fall from a skateboard 1 year later. Subsequently he had broken bones in hands and feet after substantial falls and refractured his right tibia in a fall down 5 flights of stairs. The sclerae were pale blue. Dental examination and x-rays showed typical changes of dentinogenesis imperfecta type I. The boy was at the 25th centile for height and weight. Lumbar spine x-rays showed mild osteoporosis. Analysis of the collagens produced by both gingival and skin fibroblast cultures showed the synthesis and intracellular retention of an abnormal alpha-2(I) chain that migrated faster than normal on SDS-PAGE. The denaturation temperature of the mutant protein was some 6 degrees centigrade below normal. At 37 degrees centigrade secretion of abnormal protein was not detectable, but at a lower temperature (30 degrees centigrade) some was secreted into the medium. Cyanogen bromide peptide mapping of the intracellular protein indicated a probable deletion in the N-terminal peptide. RT-PCR amplification of mRNA coding for this peptide revealed a heterozygous deletion of the 108-bp exon 21 of COL1A2. Sequencing identified a G-to-A transition in the moderately conserved +5 position of the IVS21 5-prime consensus splice site, causing the skipping of exon 21. Hybridization with allele-specific oligonucleotides showed no other family member with this base change. Since the deletion was associated with the negative allele of a PvuII polymorphism in exon 25 of COL1A2, Nicholls et al. (1996) could demonstrate that the mutant pre-mRNA was alternatively spliced, yielding both full-length and deleted transcripts. Family genotype analysis indicated that the mutation had originated in the father's gene. The father and other members of the family lacked the mutation.


.0037   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, GLY1006ALA
SNP: rs121912911, ClinVar: RCV000018806

In a patient with type III osteogenesis imperfecta (OI3; 259420), Lu et al. (1995) demonstrated a G-to-C mutation at position 3287 (exon 49) that converted the GGC codon for glycine-1006 to GCC for alanine (G1006A) in the triple-helical domain of the COL1A2 gene.

Cole and Lam (1996) described the patient originally reported by Lu et al. (1995), noting that the 3-year-old boy had some unusual features, including brachydactyly, a large arachnoid cyst arising from the right Sylvian fissure, and bilateral chronic subdural hematoma that was diagnosed and treated at 4 months of age.

Faqeih et al. (2009), who restudied the patient at 15 years of age, designated the mutation as gly1096-to-ala (GLY1096ALA).


.0038   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, GLY586VAL
ClinVar: RCV000018793, RCV000018794

In a child with osteogenesis imperfecta type III (OI3; 259420) and a substitution of glycine-586 by valine (G586V) in the triple-helical domain of the alpha-2(I) chain of type I collagen, Cole et al. (1996) found that the skeleton was severely porotic but contained lamellar bone and Haversian systems. From early childhood, structural failure of the bone resulted in the disruption of growth plates, progressive bone deformities, and severe growth retardation. Her development was prospectively recorded over 14 years. Her sclerae faded to a slightly bluish tint at 14 years of age. She had severe dentinogenesis imperfecta of her primary and secondary dentition. During the study, she did not develop basilar compression. She had mild conductive hearing loss. (The authors referred to the mutation as occurring at glycine-585 in the title, but used glycine-586 in the article. MHP.)


.0039   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, GLY751SER
SNP: rs72658176, gnomAD: rs72658176, ClinVar: RCV000018808, RCV002228039

De Paepe et al. (1997) demonstrated homozygosity for a gly751-to-ser mutation (G751S) in the COL1A2 gene in 2 sibs with type III osteogenesis imperfecta (OI3; 259420). The parents were first cousins. The heterozygous father had sustained 2 fractures after specific trauma. He was short (1.50 m), had a large head with triangular-shaped face, varus deformity and reduced mobility of the hips, and mild bowing of the lower legs. X-ray examination showed generalized osteopenia. The mother had no history of fractures, but like the father, suffered from diffuse articular pain. She was short (1.47 m) and showed generalized osteopenia on x-ray.


.0040   OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A2, IVS26DS, A-G, +3
SNP: rs72658127, ClinVar: RCV000622570, RCV001807644

Zolezzi et al. (1997) identified a splice mutation in the COL1A2 gene in a family that came to attention after ultrasonographic analysis had shown bowing and fractures of femora and tibiae in a female fetus at 25 weeks' gestation. Subtle clinical and radiologic signs of osteogenesis imperfecta (OI4; 166220), previously unrecognized, were found in the father and paternal grandmother. Linkage analysis indicated COL1A2 as the disease locus. Heteroduplex analysis of RT-PCR amplification products of COL1A2 mRNA from the proband and subsequent sequencing of the candidate region demonstrated the presence of normal transcripts and a minority of transcripts lacking exon 26 (54 bp) of COL1A2. Sequencing of PCR-amplified genomic DNA identified an A-to-G transition in the moderately conserved +3 position of the IVS26 donor splice site. Studies of dermal fibroblasts showed intracellular retention of the mutant protein. Failure to detect the shortened alpha-2 chains either in the medium or in the cell layer may have been the consequence of their instability at physiologic temperature.


.0041   COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 2

COL1A2, IVS9DS, G-A, +5
SNP: rs72656364, ClinVar: RCV000018810, RCV003764609

Nathanson et al. (1997) described a 14-year-old and his 4-generation family who had a mixed osteogenesis imperfecta Ehlers-Danlos syndrome phenotype (OIEDS2; 619120) that resulted from an exon-skipping mutation in the COL1A2 gene. The proband had short stature, hypermobility and dislocation of large and small joints, blue sclerae, soft hyperextensible skin, decreased adipose tissue, and multiple fractures. He developed subacute bacterial endocarditis on a bicuspid aortic valve, requiring valve replacement surgery. The ascending aorta showed an abrupt transition in the proximal ascending aorta from normal to an area of disruption of elastin fibers with marked medial cystic necrosis and generalized mucomyxoid changes. Other affected family members were at or below the 5th centile in height with blue sclerae, joint laxity, and/or fractures. The proband's sister had congenital dislocated hips requiring surgery. The proband had a G-to-A transition in the fifth nucleotide of intron 9 of the COL1A2 gene, which caused skipping of exon 9. The shortened collagen chain disrupted the alignment of the 3 collagen chains forming the triple helix at exon 6, the site of the N-proteinase procollagen cleavage site and lysyl crosslinking. With the malalignment at exon 6, Nathanson et al. (1997) predicted that decreased crosslinking between chains would result in decreased tensile strength and a tendency to fracture.


.0042   EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2

COL1A2, IVS5AS, A-G, -2
SNP: rs72656355, ClinVar: RCV000018811, RCV000433468, RCV002228040, RCV002276561

In 5 affected members of a family with Ehlers-Danlos syndrome type VIIB (EDSARTH2; 617821), Byers et al. (1997) identified a heterozygous A-to-G transition in intron 5 of the COL1A2 gene, resulting in the production of a protein lacking the first 5 amino acids encoded by exon 6, including the N-proteinase site and the pepsin-sensitive site. Affected individuals had dislocated hips, repeated dislocation of multiple joints, and joint laxity. No affected relatives had fractures, dental or hearing abnormalities, blue sclerae, poor wound healing, or hernias.


.0043   COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 2

COL1A2, 13.5-KB DUP
ClinVar: RCV000018812

Raff et al. (2000) described a 13.5-kb duplication involving 20 exons in the COL1A2 gene in a patient with features of osteogenesis imperfecta and Ehlers-Danlos syndrome (OIEDS2; 619120). The patient was a 22-month-old boy seen because of a history of clubfeet and bilateral congenital hip dislocation. At 22 months, the patient had a prominent forehead with an anterior fontanel measuring 3x3 cm. His sclerae were blue-gray, and his teeth had an opalescent appearance. An umbilical hernia was present. He had generalized joint hypermobility but only mild hyperextensibility of the skin. He was neurologically normal and developmentally appropriate. At the age of 5 years, he had a normal gait but frequent dislocation of the left shoulder. His umbilical hernia was still evident and was eventually excised surgically. Generalized joint hypermobility, gray sclerae, and eroded dentition remained remarkable. At 7 years of age, he sustained a fracture of the distal tibia. At 8.5 years of age, he had an advanced bone age of 11.5 years. Bone density appeared normal. Because of the nature of trimer assembly, the additional polypeptide material (477 amino acids) was located almost entirely as an amino-terminal extension of the trimer such that triple helix integrity was largely intact. This suggested that chain association at the C-terminal end of the molecule drives any expansion of the triple helix toward the N-terminal end of the protein.


.0044   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, GLY277TRP
SNP: rs72656402, ClinVar: RCV000018813

In a 9-year-old Turkish boy with severely deforming osteogenesis imperfecta (OI3; 259420), Nuytinck et al. (2000) identified a G-to-T transversion at nucleotide 1238 of the COL1A2 gene, resulting in the substitution of a glycine by a tryptophan residue at position 277 (G277Y) of the alpha-2(I) collagen chain. Nuytinck et al. (2000) noted this as the first described mutation in which a glycine residue was replaced by a tryptophan residue, which they noted was the most voluminous amino acid. Nuytinck et al. (2000) considered the nonlethal phenotype associated with this mutation, unexpected in view of the huge size of the tryptophan residue, to support the regional model of phenotypic severity for COL1A2 mutations, in which the phenotype is determined primarily by the nature of the collagen domain rather than the type of the glycine substitution involved.


.0045   EHLERS-DANLOS SYNDROME, CARDIAC VALVULAR TYPE

COL1A2, IVS11DS, G-A, +5
SNP: rs72656367, ClinVar: RCV000018814

In a patient with Ehlers-Danlos syndrome with a cardiac valvular phenotype (EDSCV; 225320), Byers (2002) identified compound heterozygosity for 2 splice site mutations in the COL1A2 gene resulting in complete failure to make pro-alpha-2 chains. One mutation, IVS11+5G-A, inactivated the normal splice site and led to the use of a normally cryptic site and the inclusion of 60 nucleotides in the mRNA derived from this allele. The sequence contained a stop codon, TAA, and, as a result, the mRNA from this allele was very unstable and in low abundance. The second mutation, IVS24+1G-C (120160.0046), also destroyed the normal donor site and led to use of a cryptic donor site upstream in exon 24 that resulted in removal of 8 nucleotides from the mRNA, a translational frameshift, and the appearance of a premature termination codon, TGA, in the sequence provided by exon 26. Again this mRNA was extremely unstable. The effects on mRNA were thought to reflect nonsense-mediated decay (NMD).

The patient described by Byers (2002) and Schwarze et al. (2004) had suffered from frequent joint dislocations and torn tendons. He was relatively short of stature and had striking loose-jointedness. At the age of 45 years, the patient had severe mitral regurgitation and moderate aortic regurgitation with borderline dilatation of the aortic root (McKusick, 2002).

Schwarze et al. (2004) reported that, following episodes of arrhythmias and atrial fibrillation, the patient described by Byers (2002) underwent mitral and aortic valve replacement surgery. Although the procedure itself was uneventful, once the prosthetic valves were placed, first the mitral annulus (not the prosthetic valve) dehisced from the ventricle, then the aortic valve separated from the atrioventricular groove, and finally there was massive leakage through the left ventricular myocardium with disintegration of the entire left ventricle, from the which the patient died.


.0046   EHLERS-DANLOS SYNDROME, CARDIAC VALVULAR TYPE

COL1A2, IVS24DS, G-C, +1
SNP: rs67162110, gnomAD: rs67162110, ClinVar: RCV000018815

For discussion of the splice site mutation in the COL1A2 gene (IVS24+1G-C) that was found in compound heterozygous state in a patient with Ehlers-Danlos syndrome with a cardiac valvular phenotype (EDSCV; 225320) by Schwarze et al. (2004), see 120160.0045.


.0047   EHLERS-DANLOS SYNDROME, CARDIAC VALVULAR TYPE

COL1A2, IVS24DS, G-A, +1
SNP: rs67162110, gnomAD: rs67162110, ClinVar: RCV000018816, RCV002276562

Hata et al. (1988) described a patient with a form of Ehlers-Danlos syndrome (EDSCV; 225320) and complete absence of COL1A2 chain and their derivatives in tissues. The patient's fibroblasts contained less than 10% of the normal mRNAs for this chain, but the DNA contained a normal number of COL1A2 genes. The patient had suffered from hyperextensibility of the skin, hypermobility of the joints, especially joints of the fingers, and proneness to scar formation since childhood. At age 35 years, she noticed easy bruisability of the skin. She complained of palpitation and shortness of breath with exertion, and mitral valve regurgitation due to prolapse of the valve was present. She also displayed slightly blue sclerae. The same patient was reported by Kojima et al. (1988), who noted that she had had mitral valve replacement. In this patient, Schwarze et al. (2004) identified compound heterozygosity for 2 splice site mutations in the COL1A2 gene: IVS24+1G-A and IVS1+717A-G (120160.0048). The patient, then aged 65 years, had soft skin and no history of fractures.


.0048   EHLERS-DANLOS SYNDROME, CARDIAC VALVULAR TYPE

COL1A2, IVS1DS, A-G, +717
SNP: rs72656354, ClinVar: RCV000018817

For discussion of the splice site mutation in the COL1A2 gene (IVS1+717A-G) that was found in compound heterozygous state in a patient with Ehlers-Danlos syndrome with a cardiac valvular phenotype (EDSCV; 225320) by Schwarze et al. (2004), see 120160.0047.


.0049   COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 2

COL1A2, IVS46DS, T-C, +2
SNP: rs72659324, ClinVar: RCV000018818

Nicholls et al. (2001) presented evidence of homozygosity for a splicing defect in the COL1A2 gene in an offspring of first-cousin parents with combined osteogenesis imperfecta and Ehlers-Danlos syndrome-2 (OIEDS2; 619120). Marked ligamentous laxity and muscle hypertonia had been noted first at her premature (28 weeks' gestation) birth. Delayed ambulation was attributed to ligamentous laxity. At the age of 9 years she was of average height but showed marked generalized joint laxity, pes planus, and valgus heels leading to a secondary shortening of the Achilles tendon. Her skin was normal, her sclerae were pale blue, and there was dental overcrowding but no dentinogenesis imperfecta. There was a history of recurrent patellar dislocations and fractures of the skull, clavicle, fingers (3), and a toe following separate minimal traumas. The proband was found to be homozygous for a T-to-C transition at nucleotide +2 of the donor splice site of IVS46. The mother, who showed some joint laxity, and a sister were carriers of the mutation; the father was not available for testing. There was no evidence of exon skipping in this case; instead, the predominant product arose from use of a cryptic donor splice site using the second and third bases of a glycine codon 17 bp upstream of the normal splice junction as the obligate GT-dinucleotide. Thus, for most of the mature mRNA, the last 17 bp of exon 46 were deleted and the resultant frameshift introduced a termination codon just 3 codons downstream.


.0050   OSTEOGENESIS IMPERFECTA, TYPE IV

COL1A2, GLY379ALA
SNP: rs121912912, ClinVar: RCV000018819, RCV002228041

In a 35-year-old woman with osteogenesis imperfecta type IV (OI4; 166220) and dentinogenesis imperfecta, which thus might be classified as OI type IVB, Johnson et al. (2002) identified a 1406G-C transversion in the COL1A2 gene, resulting in a gly379-to-ala substitution (G179A, in which the first glycine of the triple helix is referred to as the index position, or G469A when the initiator methionine is the reference point). Her phenotype was atypical in that she had persistent blue sclerae, which occurs in up to 10% of patients with OI4, and an improvement in congenital skeletal deformities. As a child, she had shortening of the limbs and severe bowing of the legs. After casting of her legs and learning to walk, however, her lower limbs showed dramatic improvement which had been maintained. Two of her children showed marked skeletal abnormalities, including femoral bowing, wormian bones, and osteopenia. The authors noted that the proband was initially thought to have kyphomelic dysplasia (211350).


.0051   EHLERS-DANLOS SYNDROME, CARDIAC VALVULAR TYPE

COL1A2, GLU1201TER
SNP: rs72659343, gnomAD: rs72659343, ClinVar: RCV000018820

In a 30-year-old man with autosomal recessive Ehlers-Danlos syndrome with a cardiac valvular phenotype (EDSCV; 225320), Schwarze et al. (2004) identified a homozygous 3601G-T transversion in exon 50 of the COL1A2 gene, resulting in a glu1201-to-ter (E1201X) mutation. The phenotypically normal parents were second cousins. He had a large secundum-type atrial septal defect, mitral valve prolapse with significant mitral regurgitation, and severe aortic valve regurgitation. His aortic root diameter at age 29 years was 36 mm, at the upper limit of normal. He developed marked left ventricular enlargement and had his aortic and mitral valves replaced with prosthetic valves, with no surgical complications. Perforation of the femoral artery and vein occurred in the course of preoperative diagnostic cardiac catheterization, and the cardiac surgeon described the tissues as extremely soft.

In a 24-year-old woman and her 12-year-old sister, born to apparently unrelated parents in a small town in southern Italy, with EDSCV, Guarnieri et al. (2019) identified homozygosity for the c.3601G-T transversion (c.3601G-T, NM_000089.3) in exon 50 of the COL1A2 gene, resulting in an E1201X mutation. The sisters had generalized joint hypermobility that was more severe in the extremities, severe flatfeet, minor skin changes, lower eyelid ectropion/ptosis, and hypoplastic distal interphalangeal creases. Cardiac involvement was progressive to moderate-severe mitral valve insufficiency in the older sister and mild in the younger sister. The aortic valve was normal in both patients. Their unaffected parents were heterozygous for the variant.


.0052   EHLERS-DANLOS SYNDROME, CARDIAC VALVULAR TYPE

COL1A2, 1-BP INS, 292C
SNP: rs797044459, ClinVar: RCV000018821

In a 6-year-old male with cardiac valvular type of Ehlers-Danlos syndrome (EDSCV; 225320), who had a clinical phenotype of the hypermobile (arthrochalasis) type of EDS, Malfait et al. (2006) found a total absence of the alpha-2 chain of type I collagen. Molecular studies demonstrated a homozygous insertion of a C (292_293insC) at codon 8 of COL1A2 exon 7. The resulting frameshift introduced a premature termination codon in the next amino acid position. Both first-cousin parents carried the same insertion in heterozygous state. Since some signs of mitral valve bulging were present already in the patient at the age of 6 years, cardiac follow-up by echocardiography was proposed for patients with complete absence of alpha-2 chains of type I collagen.


.0053   OSTEOGENESIS IMPERFECTA, TYPE II

COL1A2, GLY421ASP
SNP: rs267606741, ClinVar: RCV000018822

In a patient with lethal osteogenesis imperfecta type II (OI2; 166210), Forlino et al. (1998) identified a 1671G-A transition in the paternally-derived allele of the COL2A1 gene, resulting in a gly421-to-asp (G421D) substitution. The patient and his unaffected father carried the rare R618Q variant (120160.0020), which the authors suggested was not responsible for the OI phenotype. Forlino et al. (1998) determined that the G421D variant showed dramatic delay in the alpha-2(I) electrophoretic mobility caused by a kink in the mutated collagen chains. Rotary shadowing electron microscopy of secreted fibroblast procollagen from the patient confirmed the presence of a kink in the region of the helix containing the glycine substitution.


.0054   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, GLY1090ASP
SNP: rs267606742, ClinVar: RCV000018823

In a 17-year-old girl with osteogenesis imperfecta type III and brachydactyly (OI3; 259420), who had a left parietal subdural hematoma with no history of preceding trauma, Faqeih et al. (2009) identified a gly1090-to-asp (G1090D) substitution in exon 49 of the COL1A2 gene.


.0055   OSTEOGENESIS IMPERFECTA, TYPE III

COL1A2, GLY1099ARG
SNP: rs72659338, ClinVar: RCV000018824

In a 6.8-year-old girl with osteogenesis imperfecta type III and brachydactyly (OI3; 259420), who developed an epidural hematoma after falling from her wheelchair, Faqeih et al. (2009) identified a gly1099-to-arg (G1099R) substitution in exon 49 of the COL1A2 gene.


.0056   COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 2

COL1A2, 1-BP DEL, A, 324+4
SNP: rs1791756559, ClinVar: RCV001270302

In a female patient (P3) with combined osteogenesis imperfecta and Ehlers-Danlos syndrome-2 (OIEDS2; 619120), Malfait et al. (2013) identified a heterozygous 1-bp deletion (c.324+4delA, NM_000089.3) in the COL1A2 gene that resulted in skipping of exon 7.


.0057   COMBINED OSTEOGENESIS IMPERFECTA AND EHLERS-DANLOS SYNDROME 2

COL1A2, GLY109ASP
SNP: rs1114167416, ClinVar: RCV000490674, RCV001270303, RCV002446951

In a male patient (P4) with combined osteogenesis imperfecta and Ehlers-Danlos syndrome-2 (OIEDS2; 619120), Malfait et al. (2013) identified a heterozygous c.326G-A transition (c.326G-A, NM_00089.3) in exon 8 of the COL1A2 gene, resulting in a gly109-to-asp (G109D) substitution.


See Also:

Brebner et al. (1985); Byers et al. (1980); Dickson et al. (1985); Grobler-Rabie et al. (1985); Grobler-Rabie et al. (1985); Junien et al. (1983); Kuivaniemi et al. (1988); Myers et al. (1981); Peltonen et al. (1980); Phillips et al. (1990); Sillence et al. (1979); Weil et al. (1990); Wozney et al. (1981)

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Contributors:
Sonja A. Rasmussen - updated : 09/12/2022
Sonja A. Rasmussen - updated : 12/10/2020
Marla J. F. O'Neill - updated : 04/10/2018
Nara Sobreira - updated : 4/11/2011
Marla J. F. O'Neill - updated : 8/27/2010
Joanna S. Amberger - updated : 3/16/2010
Ada Hamosh - updated : 7/9/2008
Cassandra L. Kniffin - updated : 6/18/2008
Cassandra L. Kniffin - updated : 5/17/2007
Victor A. McKusick - updated : 9/20/2006
Victor A. McKusick - updated : 4/27/2004
Cassandra L. Kniffin - updated : 11/10/2003
Victor A. McKusick - updated : 8/26/2003
Victor A. McKusick - updated : 8/2/2001
Michael J. Wright - updated : 7/20/2001
Victor A. McKusick - updated : 2/16/2000
Victor A. McKusick - updated : 3/13/1998
Victor A. McKusick - updated : 12/11/1997
Victor A. McKusick - updated : 10/24/1997
Victor A. McKusick - updated : 9/10/1997
Victor A. McKusick - updated : 6/18/1997
Victor A. McKusick - updated : 5/16/1997
Victor A. McKusick - updated : 3/21/1997
Iosif W. Lurie - updated : 9/11/1996

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

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terry : 9/10/1997
joanna : 8/12/1997
mark : 7/16/1997
terry : 7/7/1997
terry : 6/23/1997
jenny : 6/23/1997
alopez : 6/21/1997
mark : 6/18/1997
alopez : 6/2/1997
mark : 5/19/1997
terry : 5/19/1997
terry : 5/16/1997
terry : 5/10/1997
jenny : 3/25/1997
jenny : 3/25/1997
terry : 3/21/1997
terry : 1/27/1997
jamie : 1/21/1997
terry : 1/14/1997
carol : 9/15/1996
carol : 9/11/1996
terry : 7/2/1996
terry : 7/2/1996
terry : 6/27/1996
mark : 3/4/1996
terry : 2/21/1996
carol : 3/19/1995
mimadm : 12/22/1994
terry : 7/28/1994
davew : 7/19/1994
jason : 7/14/1994
warfield : 4/8/1994