HGNC Approved Gene Symbol: COL11A2
Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38): 6:33,162,694-33,193,519 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.32 | Deafness, autosomal dominant 13 | 601868 | Autosomal dominant | 3 |
| Deafness, autosomal recessive 53 | 609706 | Autosomal recessive | 3 | |
| Fibrochondrogenesis 2 | 614524 | Autosomal dominant; Autosomal recessive | 3 | |
| Otospondylomegaepiphyseal dysplasia, autosomal dominant | 184840 | Autosomal dominant | 3 | |
| Otospondylomegaepiphyseal dysplasia, autosomal recessive | 215150 | Autosomal recessive | 3 |
Type XI collagen, a fibril-forming collagen found mainly in the cartilage extracellular matrix, is important for the integrity and development of the skeleton (summary by Lui et al., 1996).
Kimura et al. (1989) cloned human COL11A2, which encodes a deduced protein with high sequence similarity to COL11A1 (120280). By Northern blot analysis, Kimura et al. (1989) showed that COL11A2 is expressed in cartilage but not in adult liver, skin, and tendon.
Law et al. (1989, 1990) used a cosmid clone containing the COL11A2 gene as a probe in the Southern blot analysis of DNA from a panel of human/hamster somatic cell hybrids containing different numbers and combinations of human chromosomes. They concluded that the gene is located on chromosome 6, and study of a cell hybrid containing only 6q indicated that the COL11A2 gene is on 6p.
By a combination of somatic cell hybrid mapping and in situ hybridization, Hanson et al. (1989, 1989) localized the COL11A2 gene to 6p21.3. By physical mapping of the class II HLA region using pulsed field gel electrophoresis, Hanson et al. (1991) demonstrated that the COL11A2 gene is about 45 kb centromeric to HLA-DPA1 (142880) and is transcribed in the opposite (i.e., telomeric) direction.
Kimura et al. (1989) assigned the COL11A2 gene to 6p21.2 by in situ hybridization. The nucleotide sequence showed that although type XI collagen belongs to the fibril-forming class of collagens, there are substantial differences in exon sizes at the 3-prime end of the gene when comparing the COL11A2 gene with the genes for types I, II, and III collagens. It is thought that the alpha-3 chain of type XI collagen is a posttranslational variant of the type II, or cartilage, collagen subunit, i.e., is encoded by the COL2A1 gene (120140).
Stubbs et al. (1993) showed that the homologous gene in the mouse is also 'embedded' within the major histocompatibility complex on chromosome 17.
Vuoristo et al. (1995) analyzed the COL11A2 gene from 2 overlapping cosmid clones that had previously been isolated in the course of searching the human major histocompatibility region. Nucleotide sequence defined over 28,000 bp of the gene. It was shown to contain 66 exons. As with most genes for fibrillar collagens, the first intron was among the largest, and the introns at the 5-prime end of the gene were in general larger than the introns at the 3-prime end. Analysis of the exons coding for the major triple helical domain indicated that the gene structure had not evolved with the genes for the major fibrillar collagen and that there were marked differences in the number of exons, the exon sizes, and codon usage. The gene was located close to the gene for the retinoid X receptor beta (180246) in a head-to-tail arrangement similar to that previously seen with the 2 mouse genes. Also, there was marked interspecies homology in the intergenic sequences.
Lui et al. (1996) showed that COL11A2 contains at least 62 exons spanning 30.5 kb. The gene differs from other collagens in that the amino propeptide is encoded by 14 exons rather than the usual 5 to 8. The promoter is GC-rich and lacks a TATA box. The authors believed that the gene is likely to undergo alternative splicing. The gene lies within the MHC region and is only 1.1-kb from the retinoid X receptor-beta (180246) and about 40 kb from DPB2 (142880).
Melkoniemi et al. (2000) stated that in spite of partial overlap between the Stickler (see 108300), Marshall (154780), Weissenbacher-Zweymuller (OSMEDA; 184840), and otospondylomegaepiphyseal dysplasia (OSMEDB; 215150) phenotypes caused by mutations in the COL2A1 (120140), COL11A1 (120280), and COL11A2 genes, absence of eye involvement in patients carrying COL11A2 mutations is noteworthy. This was best explained by the finding that the COL11A2 gene is not expressed in the vitreous body and that the COL5A2 (120190) chain replaces the COL11A2 chain in the ocular vitreous (Mayne et al., 1993).
Otospondylomegaepiphyseal Dysplasia, Autosomal Dominant
Pihlajamaa et al. (1998) demonstrated that the original patient with Weissenbacher-Zweymuller syndrome (WZS) (Weissenbacher and Zweymuller, 1964) had a heterozygous mutation in the COL11A2 gene (120290.0004). They noted phenotypic overlap between WZS and a disorder called 'nonocular Stickler syndrome,' which was also found to be caused by heterozygous mutation in the COL11A2 gene. Pihlajamaa et al. (1998) and Spranger (1998) concluded that the disorders are identical and proposed the designation autosomal dominant otospondylomegaepiphyseal dysplasia (OSMEDA; 184840).
In affected members of the large Dutch family who had skeletal and otologic features of Stickler syndrome but no eye abnormalities, previously reported by Brunner et al. (1994), Vikkula et al. (1995) identified a heterozygous mutation in the COL11A2 gene (120290.0001).
In affected members of a family with a Stickler syndrome phenotype without eye involvement, Sirko-Osadsa et al. (1998) identified heterozygosity for a 27-bp deletion in the COL11A2 gene (120290.0003). The affected family members had sensorineural hearing loss, cleft palate/uvula, micrognathia, malar flattening, joint pains, and multiple hereditary exostoses.
Otospondylomegaepiphyseal Dysplasia, Autosomal Recessive
Vikkula et al. (1995) studied a Dutch kindred in which 3 sibs of a consanguineous mating had a severe degenerative joint disease resembling osteoarthritis that presented in early adulthood and affected predominantly the hips, knees, elbows, and shoulders (OSMEDB; 215150). Vikkula et al. (1995) found that the mutation in these sibs was a homozygous gly175-to-arg mutation of the COL11A2 gene (120290.0002). van Steensel et al. (1997) described the clinical and radiographic features of otospondylomegaepiphyseal dysplasia in these sibs.
Melkoniemi et al. (2000) reported 7 families with OSMED. All affected individuals had a remarkably similar phenotype: profound sensorineural hearing loss, skeletal dysplasia with limb shortening and large epiphyses, cleft palate, very flat face, hypoplasia of the mandible, a short nose with anteverted nares, and a flat nasal bridge. A different mutation of the COL11A2 gene was identified in each family. In 4 families, including 3 with consanguineous parents, the mutations were homozygous. Individuals in 3 other families, in which parents were nonconsanguineous, were compound heterozygous. Of the 10 identified mutations, 9 were predicted to cause premature termination of translation, and 1 was predicted to cause an in-frame deletion.
In an Egyptian brother and sister with OSMED, Temtamy et al. (2006) identified homozygosity for a 1-bp deletion in the COL11A2 gene (120290.0011). The first-cousin parents were heterozygous for the deletion; a younger brother was unaffected.
Deafness, Autosomal Dominant 13
In 2 families, 1 American and 1 Dutch, with autosomal dominant, nonsyndromic hearing loss (DFNA13; 601868) previously been mapped to 6p, McGuirt et al. (1999) identified heterozygous mutations in the COL11A2 gene (120290.0005-120290.0006) that were predicted to affect the triple-helix domain of the collagen protein. McGuirt et al. (1999) found that mice with a targeted disruption of Col11a2 also showed hearing loss. Electron microscopy of the tectorial membrane of these mice revealed loss of organization of the collagen fibrils. The findings revealed a unique ultrastructural malformation of the inner ear architecture associated with nonsyndromic hearing loss, and suggested that tectorial membrane abnormalities may be one etiology of sensorineural hearing loss primarily affecting the mid-frequencies.
Deafness, Autosomal Recessive 53
In 5 affected members of 2 sibships of a consanguineous Iranian family with nonsyndromic hearing loss (DFNB53; 609706), Chen et al. (2005) identified homozygosity for a missense mutation in the COL11A2 gene (P621T; 120290.0010). The 4 parents and 1 sib were heterozygous for the mutation.
In affected members of a Tunisian family and a Turkish family with nonsyndromic hearing loss, Chakchouk et al. (2015) identified homozygosity for 2 different missense mutations in the COL11A2 gene (120290.0014; 120290.0015) that segregated with disease in the respective families.
Fibrochondrogenesis 2
In a deceased infant with fibrochondrogenesis (FBCG2; 614524), born of consanguineous parents, Tompson et al. (2012) identified homozygosity for a splice site mutation in the COL11A2 gene (120290.0012). In another deceased infant with fibrochondrogenesis, who was born of healthy nonconsanguineous parents, they identified heterozygosity for a 9-bp deletion (120290.0013).
Associations Pending Confirmation
Among Japanese, ossification of the posterior longitudinal ligament of the spine (OPLL; 602475) is a leading cause of myelopathy, showing ectopic bone formation in the paravertebral ligament. Maeda et al. (2001) provided genetic evidence that the COL11A2 locus constitutes susceptibility for OPLL. Five distinct SNPs identified in COL11A2 were combined to construct haplotypes. A male-specific association with a COL11A2 haplotype was found with OPLL. In a case-control study of 711 Japanese individuals with OPLL and 896 controls, Horikoshi et al. (2006) found no association between 2 SNPs in the COL11A2 gene and OPLL.
In a large Dutch kindred with a phenotype resembling Stickler syndrome but without eye abnormalities (OSMEDA; 184840), which was found by Brunner et al. (1994) to map to the same region of 6p as the COL11A2 gene, Vikkula et al. (1995) found heterozygosity for a 1-bp change at the exon-intron boundary such that the intronic donor-site sequence, GTGAG, was replaced by ATGAG. This change created a novel NlaIII restriction site in the genomic sequence. The G-to-A transition resulted in a 54-bp in-frame deletion, which represented deletion of the exon 5-prime of the mutation. This exon sequence was located 108 nucleotides upstream of the junction between sequences encoding the triple-helical and C-propeptide domains of the alpha-2(XI) chain.
Vikkula et al. (1995) studied a Dutch kindred in which 3 sibs had a severe degenerative joint disease resembling osteoarthritis that presented in early adulthood and affected predominantly the hips, knees, elbows, and shoulders (OSMEDB; 215150). The spine was less severely affected, and adult height was only slightly below that of the unaffected sibs. There was increased lumbar lordosis and prominent interphalangeal joints. Short fifth metacarpals were found in all 3 sibs. The patients had distinctive facial features with midface hypoplasia with a short upturned nose, prominent eyes, depressed nasal bridge, and prominent supraorbital ridges. Sensorineural hearing loss was present from birth and required the use of hearing aids in all 3 affected sibs. None of the 3 had myopia or vitreoretinal degeneration. The parents were fourth cousins. The affected sibs were found to be homozygous for an extended haplotype of 7 CA dinucleotide repeat polymorphisms from 6p21 near the COL11A2 locus. Using conservative estimates of 0.002 for the frequency of the abnormal allele and 0.005 for the frequency of the marker haplotype, Vikkula et al. (1995) obtained a lod score of 3.09 at theta = 0.0 for linkage of the disease phenotype to 6p21. To find the mutation causing the autosomal recessive disorder, they used RT-PCR with total RNA extracted from EBV-transformed lymphoblasts, and the complete coding sequence of the COL11A2 gene was determined for 1 individual. This identified a G-to-A transition, converting a glycyl to an arginyl codon, within the triple-helical domain of the alpha-2(XI) chain. The change in sequence eliminated an MspI restriction site. Affected children were homozygous for the arginyl codon, while unaffected children were homozygous for the glycyl codon; both parents were heterozygous for the sequence change. The mutation occurred in a Gly-X-Y triplet. The clinical findings in the 3 sibs with the gly175-to-arg missense mutation were described by van Steensel et al. (1997).
In a family with a syndrome resembling Stickler syndrome but without eye anomalies (OSMEDA; 184840), Sirko-Osadsa et al. (1998) identified a heterozygous 27-bp deletion within exon 39 of the COL11A2 gene.
In the original patient with Weissenbacher-Zweymuller syndrome (WZS; Weissenbacher and Zweymuller, 1964), now designated autosomal dominant otospondylomegaepiphyseal dysplasia (OSMEDA; 184840), Pihlajamaa et al. (1998) identified heterozygosity for G-to-A transition in the COL11A2 gene that converted codon 955 from an obligate glycine (GGG) in the major triple helix of the protein to a codon for glutamate (GAG).
In affected members of an American family with autosomal dominant nonsyndromic sensorineural hearing loss (DFNA13; 601868), McGuirt et al. (1999) identified a heterozygous C-to-T missense mutation in exon 42 that predicted an arg549-to-cys amino acid substitution.
In affected members of a Dutch family with autosomal dominant nonsyndromic sensorineural deafness (DFNA13; 601868), McGuirt et al. (1999) found a heterozygous G-to-A transition in exon 31 that predicted a gly323-to-glu amino acid substitution.
In a family from Morocco with consanguineous parents, Melkoniemi et al. (2000) found that 3 children with otospondylomegaepiphyseal dysplasia (OSMEDB; 215150) were homozygous for a C-to-A transversion at nucleotide 2492 in exon 33 of the COL11A2 gene, resulting in a ser345-to-ter substitution. One of the children was described as having normal body length at birth, but short limbs with enlarged joints and stiff interphalangeal joints were noted. The radiologic features included vertebral coronal clefts, square iliac wings and a thick ischium, large metaphyses of the long bones, and enlarged epiphyses of the elbows and knees. At age 7 years, she was of nearly normal height, but disproportionate, and her palate was extremely narrow, with a double row of teeth. Eye examination revealed slight myopia.
In affected members of a 3-generation family with a disorder resembling Stickler syndrome but without eye anomalies (OSMEDA; 184840), Vuoristo et al. (2004) identified a heterozygous C-to-T transition in exon 57 of the COL11A2 gene, resulting in an arg893-to-ter (R893X) substitution. The mutation induced skipping of exon 57 in 1 allele, resulting in an in-frame deletion of 18 amino acids. Sensorineural hearing loss was present in all 3 generations. The propositus was a 4-year-old boy who had Robin sequence at birth. Both the propositus and his father had a flat malar area and nasal bridge, and the nose was upturned. The father had symptoms and radiologic findings of osteoarthritis from the age of 29 years. At age 73 years, the affected grandmother showed extensive osteoarthritic changes in the spine. Her father had undergone hip replacement in mid-adulthood.
In male twins with otospondylomegaepiphyseal dysplasia (OSMEDB; 215150), who were born to nonconsanguineous parents of northern European descent, Melkoniemi et al. (2000) identified compound heterozygous mutations in the COL11A2 gene: a 3991C-T transition, resulting in an arg845-to-ter (R845X) substitution, inherited from the father, and a splice site mutation (IVS53+5G-A) inherited from the mother.
In 5 individuals from a consanguineous Israeli Bedouin family with OSMED, who had a clinical diagnosis of autosomal recessive Weissenbacher-Zweymuller syndrome, Harel et al. (2005) identified homozygosity for the R845X mutation.
In 5 affected members of 2 sibships of a consanguineous Iranian family with nonsyndromic hearing loss (DFNB53; 609706), Chen et al. (2005) identified homozygosity for an 1861C-A transversion in exon 21 of the COL11A2 gene, resulting in a pro621-to-thr (P621T) substitution near the N terminus of the triple helical region. The 4 parents and 1 sib were heterozygous for the mutation.
In an Egyptian brother and sister with otospondylomegaepiphyseal dysplasia B (OSMEDB; 215150), Temtamy et al. (2006) identified homozygosity for a 1-bp deletion (3962delG) in exon 55 of the COL11A2 gene, resulting in a termination codon in exon 56. The first-cousin parents were heterozygous for the deletion; a younger brother was unaffected.
In a deceased infant with fibrochondrogenesis-2 (FBCG2; 614524), born of consanguineous parents, Tompson et al. (2012) identified homozygosity for a 1-bp insertion in intron 18 (+3insG) of the COL11A2 gene, predicted to result in aberrant mRNA processing. The unaffected parents were heterozygous for the mutation, as was an unaffected sib. An exon trapping splicing assay in COS-7 cells demonstrated skipping of exon 18 in RNA from the mutant construct but not from the control.
In a deceased infant with fibrochondrogenesis-2 (FBCG2; 614524), born of healthy nonconsanguineous parents, Tompson et al. (2012) identified heterozygosity for a de novo 9-bp deletion (2899_2907del9), predicted to delete 3 amino acids within the triple helical domain. The mutation was not present in the unaffected parents.
In 4 affected members of a large consanguineous Tunisian family (family FT3) with prelingual profound sensorineural hearing loss (DFNB53; 609706), Chakchouk et al. (2015) identified homozygosity for a c.109G-T transversion (c.109G-T, NM_080680.2) in the COL11A2 gene, resulting in an ala37-to-ser (A37S) substitution at a highly conserved residue within the alpha-2 helix in the NC4 domain. The mutation segregated fully with disease in the family and was not found in 113 Tunisian controls or in the Exome Variant Server or dbSNP databases. Family members who were heterozygous carriers of A37S exhibited apparently progressive sensorineural hearing loss after age 30 years.
In 2 Turkish sisters (family 262) with prelingual profound sensorineural hearing loss (DFNB53; 609706), Chakchouk et al. (2015) identified homozygosity for a c.2662C-A transversion (c.2662C-A, NM_080680.2) in the COL11A2 gene, resulting in a pro888-to-thr (P888T) substitution at a highly conserved residue in the triple helical region. The mutation was present in heterozygosity in their unaffected consanguineous parents and their unaffected sister, but was not found in 178 Turkish controls or in the Exome Variant Server or dbSNP databases.
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