Alternative titles; symbols
HGNC Approved Gene Symbol: COL9A1
Cytogenetic location: 6q13 Genomic coordinates (GRCh38): 6:70,215,061-70,303,084 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q13 | ?Epiphyseal dysplasia, multiple, 6 | 614135 | Autosomal dominant | 3 |
| Stickler syndrome, type IV | 614134 | Autosomal recessive | 3 |
Type II collagen (120140) represents about 85% of the collagen of hyaline cartilage. In addition to it, there are several minor collagens. Using a cDNA library made from chick embryo sternal cartilage mRNA, Ninomiya and Olsen (1984) isolated and characterized a cDNA that codes for one of these collagens. The unusual qualities of the molecule for which it codes included a length of only about half that of pro-alpha-1 chains and the presence of short, noncollagenous peptides containing cysteinyl residues separating its 3 collagenous domains. The cartilage-specific collagen was enumerated as type IX. Its function was unknown (Mayne et al., 1985). The triple helix of type IX collagen is composed of 3 genetically distinct polypeptide subunits--alpha-1(IX), alpha-2(IX), and alpha-3(IX). These are the products of genes whose exon structure is different from that of fibrillar collagens. Type IX collagen is also a proteoglycan. Chondroitin sulfate and dermatan sulfate chains are covalently linked to the alpha-2(IX) chain (120260).
McCormick et al. (1987) described the structure of the glycosaminoglycan attachment site of alpha-1(IX) collagen. By a combination of cDNA and peptide sequencing, they showed that the attachment region contains the sequence gly-ser-ala-asp, located within the noncollagenous domain of the alpha-2(IX) chain. The exon coding for the attachment site in the alpha-2 gene is 48 bp long, whereas the homologous alpha-1 exon is 33 bp long. The extra sequence in the alpha-2 molecule provides an explanation for the kink observed at that site in type IX molecules when examined by electron microscopy. The inserted block of amino acid residues also provides the alpha-2 chain with a serine residue, not present in alpha-1 chains, that serves as attachment site for a glycosaminoglycan side chain. Eyre et al. (1987) concluded that type IX collagen molecules are covalently crosslinked in cartilage to molecules of type II collagen.
COMP (600310) is a pentameric glycoprotein found in the extracellular matrix of cartilage, tendons, and ligaments. Using rotary shadowing electron microscopy and immobilized proteins, Holden et al. (2001) characterized the interaction between purified chick sternal cartilage type IX collagen and purified fetal bovine Comp or the isolated human COMP C-terminal domain. They identified a collagen-binding site between residues 579 and 595 of the C-terminal domain of COMP that bound each of 4 noncollagenous domains in collagen IX.
Kimura et al. (1989) described the primary structure of type IX collagen of rat and human based on cloning and sequencing of cDNA from cDNA libraries. By in situ hybridization, they demonstrated that the COL9A1 gene is located in the proximal portion of the long arm of chromosome 6 (6q12-q14), probably at 6q13. By analysis of a panel of somatic cell hybrids containing various parts of chromosome 6, Boyle et al. (1992) confirmed the assignment to 6q12-q14. Muragaki et al. (1990) demonstrated that mouse and human RNAs contain 2 types of COL9A1 transcripts based on the presence of 2 translation start codons located within 2 alternative exons. Warman et al. (1993) confirmed the mapping of COL9A1 to 6q12-q13 by fluorescence in situ hybridization and, using an interspecific backcross panel, mapped murine Col9a1 to mouse chromosome 1.
Multiple Epiphyseal Dysplasia 6
Czarny-Ratajczak et al. (2001) identified a heterozygous mutation in the COL9A1 gene (120210.0001) in affected members of a family with multiple epiphyseal dysplasia-6 (EDM6; 614135).
Stickler Syndrome Type IV
Van Camp et al. (2006) reported an autosomal recessive form of Stickler syndrome (STL4; 614134) caused by mutation in the COL9A1 gene. They described a family of Moroccan origin in which 4 children, offspring of consanguineous parents (5th degree relatives), had features of Stickler syndrome, including moderate to severe sensorineural hearing loss, moderate to high myopia with vitreoretinopathy, and epiphyseal dysplasia. Van Camp et al. (2006) considered the COL9A1 gene to be a candidate gene on the basis of structural association with collagen types II (120140) and IX (see 120210) and because of its high expression in the human inner ear indicated by cDNA microarray. Mutation analysis of the coding region of the COL9A1 gene showed a homozygous arg295-to-stop mutation (R295X; 120210.0002) in the 4 affected children.
In affected members of 2 consanguineous families segregating autosomal recessive Stickler syndrome, Nikopoulos et al. (2011) identified homozygous mutations in the COL9A1 gene. One affected boy in a Moroccan family was homozygous for the R295X mutation, and 2 affected sisters in a Turkish family were homozygous for a novel nonsense mutation (R295X; 120210.0003).
Other Associations
Loughlin et al. (2002) performed finer linkage mapping of a primary hip osteoarthritis susceptibility locus (165720) on chromosome 6 in affected sib pair families and defined an 11.4 cM female-specific interval flanked by markers D6S452 and 509-8B2, which map between 70.5 to 81.9 cM from the 6p telomere at 6p12.3-q13. As the COL9A1 gene maps within this interval, it was considered a logical candidate gene for osteoarthritis susceptibility. Loughlin et al. (2002) identified and genotyped 20 common single-nucleotide polymorphisms (SNPs) from within COL9A1 in 146 probands from the female sib pair families and in 215 age-matched unrelated female controls. None of the SNP alleles or genotypes were associated with osteoarthritis and there was no significant difference in the frequency of common SNP haplotypes between the probands and the controls. This comprehensive association analysis did not produce any evidence supporting COL9A1 as the primary osteoarthritis susceptibility locus mapped to chromosome 6.
Nakata et al. (1993) generated transgenic mice expressing a truncated alpha-1(IX) chain, which was expected to interfere with stable triple helix formation and act as a trans-dominant mutation. Mice heterozygous for the transgene developed osteoarthritis in the articular cartilage of knee joints, while mice homozygous for the mutation developed mild chondrodysplasia as well. The phenotypic severity correlated well with the level of transgene expression. Jacenko et al. (1994) interpreted these findings in mice with a dominant-negative mutation in Col9a1, as well as the observation that mice with a homozygous null mutation in the gene have an unexpectedly mild phenotype, as indicating that type IX collagen is not essential for the assembly of the cartilage extracellular matrix, although it may be important in the maintenance of structural integrity.
Fassler et al. (1994) found that mice with 'knockout' of the Col9a1 gene did not produce alpha-1(IX) mRNA or polypeptides and were born with no conspicuous skeletal abnormalities but postnatally developed early-onset osteoarthritis. Hagg et al. (1997) found that deficiency of the alpha-1 chain led to a functional knockout of all polypeptides of collagen IX, even though the Col9a2 and the Col9a3 genes were normally transcribed. Therefore, they concluded that synthesis of alpha-1(IX) polypeptides is essential for the assembly of heterotrimeric collagen IX molecules. Surprisingly, cartilage fibrils of all shapes and banding patterns found in normal newborn, adolescent, or adult mice were formed in transgenic animals, although they lacked collagen IX. Hagg et al. (1997) concluded that collagen IX is not essential, and may be functionally redundant, for fibrillogenesis in cartilage in vivo. The protein is required, however, for long-term tissue stability, presumably by mediating interactions between fibrillar and extrafibrillar macromolecules.
In a proband with autosomal dominant multiple epiphyseal dysplasia (EDM6; 614135), Czarny-Ratajczak et al. (2001) identified insertion of a T nucleotide at the donor splice site of exon 8 (IVS8+3) of the COL9A1 gene. The same insertion was found in his affected mother but not in his unaffected sister or in any of 600 control chromosomes tested. RNA was isolated from lymphoblasts of the proband and was reverse transcribed, PCR amplified, and analyzed on agarose gels. Two major bands were noted, one corresponding to the control band and one approximately 150 bp shorter. One or more minor bands were also seen. Sequencing of these bands indicated that there were at least 3 splicing defects leading to in-frame deletions of the COL3 domain of the alpha1(IX) chain: one lacking sequences for exon 8 (25 amino acids), one lacking sequences for exon 10 (21 amino acids), and one lacking sequences for both exons 8 and 10 (46 amino acids).
In 4 affected sibs in a consanguineous Moroccan family segregating Stickler syndrome type IV (STL4; 614134), Van Camp et al. (2006) identified homozygosity for an arg295-to-stop (R295X) mutation in exon 9 the COL9A1 gene. The parents and 4 unaffected children were heterozygous carriers of the mutation. Two unaffected children were homozygous for the wildtype allele.
Nikopoulos et al. (2011) identified homozygosity for a c.883C-T transition in the COL9A1 gene, resulting in a R295X mutation, in a boy with Stickler syndrome, who was born to consanguineous Moroccan parents.
In 2 affected sisters in a consanguineous Turkish family segregating Sticker syndrome (STL4; 614134), Nikopoulos et al. (2011) identified homozygosity for a c.1519C-T transition in the COL9A1 gene, resulting in an arg507-to-ter (R507X) substitution. The unaffected parents and 2 unaffected sisters were heterozygous for the mutation.
Boyle, J. M., Hey, Y., Myers, K., Stern, P. L., Grzeschik, F.-H., Ikehara, Y., Misumi, Y., Fox, M. Regional localization of a trophoblast antigen-related sequence and 16 other sequences to human chromosome 6q using somatic cell hybrids. Genomics 12: 693-698, 1992. [PubMed: 1572643] [Full Text: https://doi.org/10.1016/0888-7543(92)90296-5]
Czarny-Ratajczak, M., Lohiniva, J., Rogala, P., Kozlowski, K., Perala, M., Carter, L., Spector, T. D., Kolodziej, L., Seppanen, U., Glazar, R., Krolewski, J., Latos-Bielenska, A., Ala-Kokko, L. A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity. Am. J. Hum. Genet. 69: 969-980, 2001. [PubMed: 11565064] [Full Text: https://doi.org/10.1086/324023]
Eyre, D. R., Apon, S., Wu, J.-J., Ericsson, L. H., Walsh, K. A. Collagen type IX: evidence for covalent linkages to type II collagen in cartilage. FEBS Lett. 220: 337-341, 1987. [PubMed: 3609327] [Full Text: https://doi.org/10.1016/0014-5793(87)80842-6]
Fassler, R., Schnegelsberg, P. N. J., Dausman, J., Shinya, T., Muragaki, Y., McCarthy, M. T., Olsen, B. R., Jaenisch, R. Mice lacking alpha 1 (IX) collagen develop noninflammatory degenerative joint disease Proc. Nat. Acad. Sci. 91: 5070-5074, 1994. [PubMed: 8197187] [Full Text: https://doi.org/10.1073/pnas.91.11.5070]
Hagg, R., Hedbom, E., Mollers, U., Aszodi, A., Fassler, R., Bruckner, P. Absence of the alpha-1(IX) chain leads to a functional knock-out of the entire collagen IX protein in mice. J. Biol. Chem. 272: 20650-20654, 1997. [PubMed: 9252382] [Full Text: https://doi.org/10.1074/jbc.272.33.20650]
Holden, P., Meadows, R. S., Chapman, K. L., Grant, M. E., Kadler, K. E., Briggs, M. D. Cartilage oligomeric matrix protein interacts with type IX collagen, and disruptions to these interactions identify a pathogenetic mechanism in a bone dysplasia family. J. Biol. Chem. 276: 6046-6055, 2001. [PubMed: 11087755] [Full Text: https://doi.org/10.1074/jbc.M009507200]
Jacenko, O., Olsen, B. R., Warman, M. L. Of mice and men: heritable skeletal disorders. (Editorial) Am. J. Hum. Genet. 54: 163-168, 1994. [PubMed: 8304335]
Kimura, T., Mattei, M.-G., Stevens, J. W., Goldring, M. B., Ninomiya, Y., Olsen, B. R. Molecular cloning of rat and human type IX collagen cDNA and localization of the alpha1(IX) gene on the human chromosome 6. Europ. J. Biochem. 179: 71-78, 1989. [PubMed: 2465149] [Full Text: https://doi.org/10.1111/j.1432-1033.1989.tb14522.x]
Loughlin, J., Mustafa, Z., Dowling, B., Southam, L., Marcelline, L., Raina, S. S., Ala-Kokko, L., Chapman, K. Finer linkage mapping of a primary hip osteoarthritis susceptibility locus on chromosome 6. Europ. J. Hum. Genet. 10: 562-568, 2002. [PubMed: 12173034] [Full Text: https://doi.org/10.1038/sj.ejhg.5200848]
Mayne, R., van der Rest, M., Ninomiya, Y., Olsen, B. R. The structure of type IX collagen. Ann. N.Y. Acad. Sci. 460: 38-46, 1985. [PubMed: 3868958] [Full Text: https://doi.org/10.1111/j.1749-6632.1985.tb51155.x]
McCormick, D., van der Rest, M., Goodship, J., Lozano, G., Ninomiya, T., Olsen, B. R. Structure of the glycosaminoglycan domain in the type IX collagen-proteoglycan. Proc. Nat. Acad. Sci. 84: 4044-4048, 1987. [PubMed: 3473493] [Full Text: https://doi.org/10.1073/pnas.84.12.4044]
Muragaki, Y., Nishimura, I., Henney, A., Ninomiya, Y., Olsen, B. R. The alpha-1(IX) collagen gene gives rise to two different transcripts in both mouse embryonic and human fetal RNA. Proc. Nat. Acad. Sci. 87: 2400-2404, 1990. [PubMed: 1690886] [Full Text: https://doi.org/10.1073/pnas.87.7.2400]
Nakata, K., Ono, K., Miyazaki, J., Olsen, B. R., Muragaki, Y., Adachi, E., Yamamura, K., Kimura, T. Osteoarthritis associated with mild chondrodysplasia in transgenic mice expressing alpha-1(IX) collagen chains with a central deletion. Proc. Nat. Acad. Sci. 90: 2870-2874, 1993. [PubMed: 8464901] [Full Text: https://doi.org/10.1073/pnas.90.7.2870]
Nikopoulos, K., Schrauwen, I., Simon, M., Collin, R. W. J., Veckeneer, M., Keymolen, K., Van Camp, G., Cremers, F. P. M., van den Born, L. I. Autosomal recessive Stickler syndrome in two families is caused by mutations in the COL9A1 gene. Invest. Ophthal. Vis. Sci. 52: 4774-4779, 2011. [PubMed: 21421862] [Full Text: https://doi.org/10.1167/iovs.10-7128]
Ninomiya, Y., Olsen, B. R. Synthesis and characterization of cDNA encoding a cartilage-specific short collagen. Proc. Nat. Acad. Sci. 81: 3014-3018, 1984. [PubMed: 6328487] [Full Text: https://doi.org/10.1073/pnas.81.10.3014]
Van Camp, G., Snoeckx, R. L., Hilgert, N., van den Ende, J., Fukuoka, H., Wagatsuma, M., Suzuki, H., Smets, R. M. E., Vanhoenacker, F., Declau, F., Van De Heyning, P., Usami, S. A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene. Am. J. Hum. Genet. 79: 449-457, 2006. [PubMed: 16909383] [Full Text: https://doi.org/10.1086/506478]
Warman, M. L., Tiller, G. E., Polumbo, P. A., Seldin, M. F., Rochelle, J. M., Knoll, J. H. M., Cheng, S.-D., Olsen, B. R. Physical and linkage mapping of the human and murine genes for the alpha-1 chain of type IX collagen (COL9A1). Genomics 17: 694-698, 1993. [PubMed: 8244386] [Full Text: https://doi.org/10.1006/geno.1993.1391]