Collagen, type II, alpha 1

COL2A1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1U5M, 2FSE, 2SEB
Identifiers
Aliases	COL2A1, AOM, COL11A3, Cartilage collagen, ANFH, STL1, collagen type II alpha 1, collagen type II alpha 1 chain, SEDC, Collagen II
External IDs	OMIM: 120140; MGI: 88452; HomoloGene: 55607; GeneCards: COL2A1; OMA:COL2A1 - orthologs
Gene location (Human) Chr. Chromosome 12 (human) Band 12q13.11 Start 47,972,967 bp End 48,004,554 bp
Gene location (Mouse) Chr. Chromosome 15 (mouse) Band 15 F1|15 53.97 cM Start 97,873,483 bp End 97,902,576 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in tibia cartilage tissue corpus epididymis trachea sperm trabecular bone tail of epididymis testicle pituitary gland gonad Top expressed in tibiofemoral joint vestibular sensory epithelium human fetus cartilage organ otic vesicle saccule set of bones of free part of upper limb trachea hand nasal septum More reference expression data BioGPS n/a
Gene ontology Molecular function identical protein binding platelet-derived growth factor binding extracellular matrix structural constituent conferring tensile strength extracellular matrix structural constituent metal ion binding MHC class II protein binding proteoglycan binding Cellular component endoplasmic reticulum lumen collagen type II trimer collagen extracellular matrix cytoplasm basement membrane extracellular space extracellular region collagen-containing extracellular matrix Biological process proteoglycan metabolic process central nervous system development endochondral ossification chondrocyte differentiation collagen fibril organization ossification limb morphogenesis otic vesicle development notochord development negative regulation of extrinsic apoptotic signaling pathway in absence of ligand heart morphogenesis inner ear morphogenesis inner ear development tissue homeostasis regulation of immune response cartilage development involved in endochondral bone morphogenesis hearing skeletal system development collagen catabolic process regulation of gene expression bone development extracellular matrix organization skeletal system morphogenesis cellular response to BMP stimulus visual perception roof of mouth development embryonic skeletal joint morphogenesis cartilage development limb bud formation cartilage condensation anterior head development Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1280 12824 Ensembl ENSG00000139219 ENSMUSG00000022483 UniProt P02458 P28481 RefSeq (mRNA) NM_001844 NM_033150 NM_001113515 NM_031163 RefSeq (protein) NP_001835 NP_149162 NP_001106987 NP_112440 Location (UCSC) Chr 12: 47.97 – 48 Mb Chr 15: 97.87 – 97.9 Mb PubMed search
Wikidata
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Collagen, type II, alpha 1 (primary osteoarthritis, spondyloepiphyseal dysplasia, congenital), also known as COL2A1, is a human gene that provides instructions for the production of the pro-alpha1(II) chain of type II collagen.

Gene

The COL2A1 gene is located on the long (q) arm of chromosome 12 between positions 13.11 and 13.2, from base pair 46,653,017 to base pair 46,684,527. The expression of COL2A1 is regulated by SOX-9 and retrotransposon gag-like-3 gene RTL3 in chondrocytes.

There are two transcripts identified for this gene.

Function

This gene encodes the alpha-1 chain of type II collagen, a fibrillar collagen found in cartilage and the vitreous humor of the eye.

Type II collagen, which adds structure and strength to connective tissues, is found primarily in cartilage, the jelly-like substance that fills the eyeball (the vitreous), the inner ear, and the center portion of the discs between the vertebrae in the spine (nucleus pulposus). Three pro-alpha1(II) chains twist together to form a triple-stranded, ropelike procollagen molecule. These procollagen molecules must be processed by enzymes in the cell. Once these molecules are processed, they leave the cell and arrange themselves into long, thin fibrils that cross-link to one another in the spaces around cells. The cross-linkages result in the formation of very strong mature type II collagen fibers.

Clinical significance

Mutations in the COL2A1 gene are associated with achondrogenesis, chondrodysplasia, early onset familial osteoarthritis, SED congenita, Langer-Saldino achondrogenesis, Kniest dysplasia, Stickler syndrome, and spondyloepimetaphyseal dysplasia Strudwick type. In addition, defects in processing chondrocalcin, a calcium binding protein that is the C-propeptide of this collagen molecule, are also associated with chondrodysplasia.

Achondrogenesis type 2

Several kinds of mutations in the COL2A1 gene are responsible for Achondrogenesis type 2. These include missing pieces of the gene, substitution of the amino acid glycine with another amino acid, or changes that result in truncated proteins. All these mutations disrupt the production of mature type II collagen, affecting tissues rich in this collagen.

Platyspondylic lethal skeletal dysplasia, Torrance type

Fewer than 10 COL2A1 mutations have been identified in people with Platyspondylic lethal skeletal dysplasia, Torrance type. Most result in a single amino acid change in the pro-alpha1(II) chain, producing an abnormal chain that cannot be incorporated into collagen fibers. This leads to reduced collagen production and skeletal abnormalities such as short limbs, small chest, flattened vertebrae, and short fingers and toes.

Hypochondrogenesis

Hypochondrogenesis is caused by various COL2A1 mutations, including deletions, glycine substitutions, and truncations. These interfere with the formation of mature, triple-stranded type II collagen molecules, affecting collagen-rich tissues.

Kniest dysplasia

Most mutations responsible for Kniest dysplasia result in abnormally short pro-alpha1(II) collagen chains that combine with normal-length chains, producing shorter-than-normal collagen molecules. This results in the characteristic features of Kniest dysplasia.

Spondyloepimetaphyseal dysplasia

All known COL2A1 mutations in Spondyloepimetaphyseal dysplasia, Strudwick type replace glycine with another amino acid in the pro-alpha1(II) chain, disrupting the formation of stable, triple-stranded collagen molecules.

Spondyloepiphyseal dysplasia congenita is caused by several types of COL2A1 mutations, including incorrect amino acid substitutions and truncated pro-alpha1(II) chains, impairing the formation of mature collagen molecules.

In Spondyloperipheral dysplasia, COL2A1 mutations produce a truncated pro-alpha1(II) chain that cannot be incorporated into collagen fibers. The abnormal chains accumulate in cartilage cells, disrupting bone development and resulting in flattened vertebrae and short digits.

Stickler syndrome

Several COL2A1 mutations cause Stickler syndrome, often leading to the production of a truncated protein that cannot be incorporated into collagen fibers. Many mutations introduce premature stop signals, resulting in a 50% reduction of pro-alpha1(II) collagen chains and underproduction of type II collagen in cartilage.

Osteoarthritis risk

Variations in the COL2A1 gene may increase susceptibility to osteoarthritis in some individuals. These variations alter amino acids in the pro-alpha1(II) chain, potentially affecting collagen fiber integrity in joint cartilage and contributing to degenerative joint disease.

Further reading

• Chan D, Cole WG, Chow CW, Mundlos S, Bateman JF (January 1995). "A COL2A1 mutation in achondrogenesis type II results in the replacement of type II collagen by type I and III collagens in cartilage". The Journal of Biological Chemistry. 270 (4): 1747–1753. doi:10.1074/jbc.270.4.1747. PMID 7829510.
• Cheah KS, Stoker NG, Griffin JR, Grosveld FG, Solomon E (May 1985). "Identification and characterization of the human type II collagen gene (COL2A1)". Proceedings of the National Academy of Sciences of the United States of America. 82 (9): 2555–2559. Bibcode:1985PNAS...82.2555C. doi:10.1073/pnas.82.9.2555. PMC 397602. PMID 3857598.
• Donoso LA, Edwards AO, Frost AT, Ritter R, Ahmad N, Vrabec T, et al. (2003). "Clinical variability of Stickler syndrome: role of exon 2 of the collagen COL2A1 gene". Survey of Ophthalmology. 48 (2): 191–203. doi:10.1016/S0039-6257(02)00460-5. PMID 12686304.
• Fernandes RJ, Wilkin DJ, Weis MA, Wilcox WR, Cohn DH, Rimoin DL, et al. (July 1998). "Incorporation of structurally defective type II collagen into cartilage matrix in kniest chondrodysplasia". Archives of Biochemistry and Biophysics. 355 (2): 282–290. doi:10.1006/abbi.1998.0745. PMID 9675039.
• Ikeda T, Mabuchi A, Fukuda A, Kawakami A, Ryo Y, Yamamoto S, et al. (July 2002). "Association analysis of single nucleotide polymorphisms in cartilage-specific collagen genes with knee and hip osteoarthritis in the Japanese population". Journal of Bone and Mineral Research : The Official Journal of the American Society for Bone and Mineral Research. 17 (7): 1290–1296. doi:10.1359/jbmr.2002.17.7.1290. PMID 12096843. S2CID 31291501.
• Körkkö J, Cohn DH, Ala-Kokko L, Krakow D, Prockop DJ (May 2000). "Widely distributed mutations in the COL2A1 gene produce achondrogenesis type II/hypochondrogenesis". American Journal of Medical Genetics. 92 (2): 95–100. doi:10.1002/(SICI)1096-8628(20000515)92:2<95::AID-AJMG3>3.0.CO;2-9. PMID 10797431.
• Meulenbelt I, Bijkerk C, De Wildt SC, Miedema HS, Breedveld FC, Pols HA, et al. (September 1999). "Haplotype analysis of three polymorphisms of the COL2A1 gene and associations with generalised radiological osteoarthritis". Annals of Human Genetics. 63 (Pt 5): 393–400. doi:10.1046/j.1469-1809.1999.6350393.x. PMID 10735581. S2CID 21918163.
• Mortier GR, Weis M, Nuytinck L, King LM, Wilkin DJ, De Paepe A, et al. (April 2000). "Report of five novel and one recurrent COL2A1 mutations with analysis of genotype-phenotype correlation in patients with a lethal type II collagen disorder". Journal of Medical Genetics. 37 (4): 263–271. doi:10.1136/jmg.37.4.263. PMC 1734564. PMID 10745044.
• Richards AJ, Baguley DM, Yates JR, Lane C, Nicol M, Harper PS, et al. (November 2000). "Variation in the vitreous phenotype of Stickler syndrome can be caused by different amino acid substitutions in the X position of the type II collagen Gly-X-Y triple helix". American Journal of Human Genetics. 67 (5): 1083–1094. doi:10.1016/S0002-9297(07)62938-3. PMC 1288550. PMID 11007540.
• Snead MP, Yates JR (May 1999). "Clinical and Molecular genetics of Stickler syndrome". Journal of Medical Genetics. 36 (5): 353–359. doi:10.1136/jmg.36.5.353. PMC 1734362. PMID 10353778.
• Tiller GE, Polumbo PA, Weis MA, Bogaert R, Lachman RS, Cohn DH, et al. (September 1995). "Dominant mutations in the type II collagen gene, COL2A1, produce spondyloepimetaphyseal dysplasia, Strudwick type". Nature Genetics. 11 (1): 87–89. doi:10.1038/ng0995-87. PMID 7550321. S2CID 24826973.
• Tysoe C, Saunders J, White L, Hills N, Nicol M, Evans G, et al. (September 2003). "A glycine to aspartic acid substitution of COL2A1 in a family with the Strudwick variant of spondyloepimetaphyseal dysplasia". QJM : Monthly Journal of the Association of Physicians. 96 (9): 663–671. doi:10.1093/qjmed/hcg112. PMID 12925722.
• Weis MA, Wilkin DJ, Kim HJ, Wilcox WR, Lachman RS, Rimoin DL, et al. (February 1998). "Structurally abnormal type II collagen in a severe form of Kniest dysplasia caused by an exon 24 skipping mutation". The Journal of Biological Chemistry. 273 (8): 4761–4768. doi:10.1074/jbc.273.8.4761. PMID 9468540.
• Wilkin DJ, Artz AS, South S, Lachman RS, Rimoin DL, Wilcox WR, et al. (July 1999). "Small deletions in the type II collagen triple helix produce kniest dysplasia". American Journal of Medical Genetics. 85 (2): 105–112. doi:10.1002/(SICI)1096-8628(19990716)85:2<105::AID-AJMG2>3.0.CO;2-Z. PMID 10406661.
• Zabel B, Hilbert K, Stöss H, Superti-Furga A, Spranger J, Winterpacht A (May 1996). "A specific collagen type II gene (COL2A1) mutation presenting as spondyloperipheral dysplasia". American Journal of Medical Genetics. 63 (1): 123–128. doi:10.1002/(SICI)1096-8628(19960503)63:1<123::AID-AJMG22>3.0.CO;2-P. PMID 8723097.
• Zankl A, Neumann L, Ignatius J, Nikkels P, Schrander-Stumpel C, Mortier G, et al. (February 2005). "Dominant negative mutations in the C-propeptide of COL2A1 cause platyspondylic lethal skeletal dysplasia, torrance type, and define a novel subfamily within the type 2 collagenopathies". American Journal of Medical Genetics. Part A. 133A (1): 61–67. doi:10.1002/ajmg.a.30531. PMID 15643621. S2CID 24925027.
• Zankl A, Zabel B, Hilbert K, Wildhardt G, Cuenot S, Xavier B, et al. (August 2004). "Spondyloperipheral dysplasia is caused by truncating mutations in the C-propeptide of COL2A1". American Journal of Medical Genetics. Part A. 129A (2): 144–148. doi:10.1002/ajmg.a.30222. PMID 15316962. S2CID 22472125.

External links

• GeneReviews/NCBI/NIH/UW entry on Stickler Syndrome
• COL2A1 at Genetics Home Reference
• small deletion defects
• nucleotide substitutions
• Definition of COL2A1 Archived 2012-08-09 at the Wayback Machine
• GeneCard