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Gene Review

COL2A1  -  collagen, type II, alpha 1

Homo sapiens

Synonyms: ANFH, AOM, Alpha-1 type II collagen, COL11A3, Collagen alpha-1(II) chain, ...
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Disease relevance of COL2A1


Psychiatry related information on COL2A1

  • Gender, type, and size of housing, insulation standard of housing, daycare, exposure to passive cigarette smoking, and dietary habits were not associated with AOM, rAOM, or COM in the surveyed children [6].

High impact information on COL2A1

  • These results demonstrate that COL2A1 expression is directly regulated by SOX9 protein in vivo and implicate abnormal regulation of COL2A1 during, chondrogenesis as a cause of the skeletal abnormalities associated with campomelic dysplasia [7].
  • Furthermore, ectopic expression of Sox9 trans-activates both a COL2A1-driven reporter gene and the endogenous Col2a1 gene in transgenic mice [7].
  • Our data support the hypothesis that some cases, if not all cases, of this distinctive chondrodysplasia result from dominant mutations in COL2A1, thus expanding the clinical spectrum of phenotypes associated with this gene [8].
  • Genetic linkage of a polymorphism in the type II procollagen gene (COL2A1) to primary osteoarthritis associated with mild chondrodysplasia [9].
  • These cell lines also expressed reporter gene constructs containing regulatory sequences (-577/+3,428 bp) of the type II collagen gene (COL2A1) in transient transfection experiments, and IL-1 beta suppressed this expression by 50-80% [10].

Chemical compound and disease context of COL2A1


Biological context of COL2A1


Anatomical context of COL2A1

  • Restriction endonuclease analysis of DNA from human-rodent hybrid cell lines in conjunction with in situ hybridization of human metaphasic chromosomes have shown that the gene coding for the pro alpha 1 chain of type II collagen (COL2A1) is located on chromosome 12 in the segment 12q131----12q132 [19].
  • Cultured dermal fibroblasts were shown, using amplification of cDNA by the polymerase chain reaction, to produce very low levels of spliced transcripts from the COL2A1 gene that encodes the cartilage-specific alpha 1(II) chains of type II collagen [1].
  • In this study, it was confirmed that the mRNA expression of ra-a47 and COL2A1, a type II collagen gene, was upregulated on stimulation with transforming growth factor (TGF) beta in chondrocytes [20].
  • METHODS: Clinical examination of the family and linkage analysis using markers flanking COL2A1 and COL11A1, the known loci for Stickler syndrome; mutation screening of COL2A1; construction of splicing reporter minigenes and transfection into cultured cells; and RT-PCR analysis of reporter specific transcripts [3].
  • Transcription of the type-II procollagen gene (COL2A1) is very specifically restricted to a limited number of tissues, particularly cartilages [21].

Associations of COL2A1 with chemical compounds

  • The p38 MAPK-selective inhibitor, SB203580, partially reversed IL-1beta-induced inhibition of COL2A1 mRNA levels and COL2A1-luciferase reporter gene expression [22].
  • However, in contrast, inflammatory cytokines such as tumor necrosis factor (TNF) alpha, interferon (IFN) beta, and interleukin (IL)-6 downregulated the expression of ra-a47 mRNA, whereas the expression of COL2A1 mRNA was not repressed, or even upregulated, in HCS-2/8 cells [20].
  • Several mutations causing Stickler syndrome have been found in the COL2A1 gene, and one mutation causing Stickler syndrome and one causing Marshall syndrome have been detected in the COL11A1 gene [23].
  • DNA sequencing showed a transition of C2913T in exon 41 of one allele of the COL2A1 gene resulting in the substitution of arginine 789 by cysteine in the alpha 1 (II) chain [24].
  • Linkage to the collagen COL2A1 locus was demonstrated and a cytosine to adenosine transition identified within exon 2, leading to the creation of a stop codon at position 86 (Cys86Stop) [25].

Physical interactions of COL2A1

  • Nevertheless, IL-1 beta decreased the binding activity of both Sp1 and Sp3 to the 63-bp short COL2A1 promoter, suggesting that the cytokine exerts a post-transcriptional regulatory mechanism on Sp1 and Sp3 gene expressions [26].

Regulatory relationships of COL2A1

  • Transfection of decoy Sp-binding oligonucleotides corroborated the implication of the proximal promoter in the TGF-beta1-induced inhibition of COL2A1 gene transcription [27].
  • These studies also show, for the first time, that p38 MAPK is one of the signals required for IL-1beta-induced inhibition of COL2A1 gene expression [22].
  • IL-1 beta down-regulates COL2A1 gene transcription through a -41/-33 bp sequence that binds a multimeric complex including Sp1 and Sp3 transcription factors [26].
  • A 1.9-Kb 5' fragment from the human COL1A1 gene drives inappropriate expression of the human COL2A1 gene in tissues of transgenic mice that normally express only the COL1A1 gene [28].

Other interactions of COL2A1

  • These findings suggest that TGF-beta1 inhibition of COL2A1 gene transcription in RAC is mediated by an increase of the Sp3/Sp1 ratio and by the repression of Sp1 transactivating effects on that gene [27].
  • We identified highly conserved sequence elements upstream of the AAUAAA in three human collagen genes, COL1A1, COL1A2, and COL2A1, and demonstrate that these upstream sequence elements (USEs) influence polyadenylation efficiency [29].
  • Similarly, COL2A1 expression in P9 cells increased fivefold compared to P4 cells, while COL10A1 levels remained unchanged [30].
  • These results suggest that SOX9 is not the key regulator of COL2A1 promoter activity in human adult articular chondrocytes [31].
  • The COMP gene mutation (C348R), while not previously published, is typical of those in PSACH patients, whereas the COL2A1 mutation (T1370M) is somewhat atypical, as it predicts an amino acid change within the carboxyl-terminal region of the protein [32].

Analytical, diagnostic and therapeutic context of COL2A1

  • The COL2A1 gene was amplified as five overlapping PCR products [33].
  • This was confirmed by sequence analysis of amplified COL2A1 cDNA, which revealed a single nucleotide substitution (GGA-->GAA) in 5 of 10 clones [34].
  • The same allele shows reduced expression in all three patients, and this allele is more frequent in a well-defined OA population than in a control group, suggesting the possible existence of a rare COL2A1 allele that predisposes to OA [35].
  • Sixteen family members underwent a complete physical examination, anthropometric measurements, radiographic studies of the spine and peripheral joints, and analysis of the type II procollagen gene (COL2A1) [36].
  • Our findings demonstrate heteroduplex analysis of the COL2A1 VNTR to be a robust and highly informative genetic marker system [37].


  1. Low basal transcription of genes for tissue-specific collagens by fibroblasts and lymphoblastoid cells. Application to the characterization of a glycine 997 to serine substitution in alpha 1(II) collagen chains of a patient with spondyloepiphyseal dysplasia. Chan, D., Cole, W.G. J. Biol. Chem. (1991) [Pubmed]
  2. Linkage analysis of five fibrillar collagen loci in a large French Marfan syndrome family. Boileau, C., Jondeau, G., Bonaiti, C., Coulon, M., Delorme, G., Dubourg, O., Bourdarias, J.P., Junien, C. J. Med. Genet. (1990) [Pubmed]
  3. A novel mutation of COL2A1 resulting in dominantly inherited rhegmatogenous retinal detachment. Richards, A.J., Meredith, S., Poulson, A., Bearcroft, P., Crossland, G., Baguley, D.M., Scott, J.D., Snead, M.P. Invest. Ophthalmol. Vis. Sci. (2005) [Pubmed]
  4. Molecular genetics of the human chondrodysplasias-1995. Horton, W.A. Eur. J. Hum. Genet. (1995) [Pubmed]
  5. Boy with syndactylies, macrocephaly, and severe skeletal dysplasia: not a new syndrome, but two dominant mutations (GLI3 E543X and COL2A1 G973R) in the same individual. Sobetzko, D., Eich, G., Kalff-Suske, M., Grzeschik, K.H., Superti-Furga, A. Am. J. Med. Genet. (2000) [Pubmed]
  6. Otitis media in Greenland. Studies on historical, epidemiological, microbiological, and immunological aspects. Homøe, P. International journal of circumpolar health. (2001) [Pubmed]
  7. SOX9 directly regulates the type-II collagen gene. Bell, D.M., Leung, K.K., Wheatley, S.C., Ng, L.J., Zhou, S., Ling, K.W., Sham, M.H., Koopman, P., Tam, P.P., Cheah, K.S. Nat. Genet. (1997) [Pubmed]
  8. Dominant mutations in the type II collagen gene, COL2A1, produce spondyloepimetaphyseal dysplasia, Strudwick type. Tiller, G.E., Polumbo, P.A., Weis, M.A., Bogaert, R., Lachman, R.S., Cohn, D.H., Rimoin, D.L., Eyre, D.R. Nat. Genet. (1995) [Pubmed]
  9. Genetic linkage of a polymorphism in the type II procollagen gene (COL2A1) to primary osteoarthritis associated with mild chondrodysplasia. Knowlton, R.G., Katzenstein, P.L., Moskowitz, R.W., Weaver, E.J., Malemud, C.J., Pathria, M.N., Jimenez, S.A., Prockop, D.J. N. Engl. J. Med. (1990) [Pubmed]
  10. Interleukin-1 beta-modulated gene expression in immortalized human chondrocytes. Goldring, M.B., Birkhead, J.R., Suen, L.F., Yamin, R., Mizuno, S., Glowacki, J., Arbiser, J.L., Apperley, J.F. J. Clin. Invest. (1994) [Pubmed]
  11. Mutation in type II procollagen (COL2A1) that substitutes aspartate for glycine alpha 1-67 and that causes cataracts and retinal detachment: evidence for molecular heterogeneity in the Wagner syndrome and the Stickler syndrome (arthro-ophthalmopathy). Körkkö, J., Ritvaniemi, P., Haataja, L., Kääriäinen, H., Kivirikko, K.I., Prockop, D.J., Ala-Kokko, L. Am. J. Hum. Genet. (1993) [Pubmed]
  12. A single base mutation in the type II procollagen gene (COL2A1) that converts glycine alpha 1-247 to serine in a family with late-onset spondyloepiphyseal dysplasia. Ritvaniemi, P., Sokolov, B.P., Williams, C.J., Considine, E., Yurgenev, L., Meerson, E.M., Ala-Kokko, L., Prockop, D.J. Hum. Mutat. (1994) [Pubmed]
  13. A human COL2A1 gene with an Arg519Cys mutation causes osteochondrodysplasia in transgenic mice. Sahlman, J., Pitkänen, M.T., Prockop, D.J., Arita, M., Li, S.W., Helminen, H.J., Långsjö, T.K., Puustjärvi, K., Lammi, M.J. Arthritis Rheum. (2004) [Pubmed]
  14. Reexpression of type IIA procollagen by adult articular chondrocytes in osteoarthritic cartilage. Aigner, T., Zhu, Y., Chansky, H.H., Matsen, F.A., Maloney, W.J., Sandell, L.J. Arthritis Rheum. (1999) [Pubmed]
  15. Familial calcium crystal diseases: what have we learned? Maldonado, I., Reginato, A.M., Reginato, A.J. Current opinion in rheumatology. (2001) [Pubmed]
  16. 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. Richards, A.J., Baguley, D.M., Yates, J.R., Lane, C., Nicol, M., Harper, P.S., Scott, J.D., Snead, M.P. Am. J. Hum. Genet. (2000) [Pubmed]
  17. Chromosomal assignments of the genes coding for human types II, III, and IV collagen: a dispersed gene family. Solomon, E., Hiorns, L.R., Spurr, N., Kurkinen, M., Barlow, D., Hogan, B.L., Dalgleish, R. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  18. A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene. Van Camp, G., Snoeckx, R.L., Hilgert, N., van den Ende, J., Fukuoka, H., Wagatsuma, M., Suzuki, H., Smets, R.M., Vanhoenacker, F., Declau, F., Van de Heyning, P., Usami, S. Am. J. Hum. Genet. (2006) [Pubmed]
  19. Further evidence for the dispersion of the human fibrillar collagen genes. Huerre-Jeanpierre, C., Mattei, M.G., Weil, D., Grzeschik, K.H., Chu, M.L., Sangiorgi, F.O., Sobel, M.E., Ramirez, F., Junien, C. Am. J. Hum. Genet. (1986) [Pubmed]
  20. Change in cellular localization of a rheumatoid arthritis-related antigen (RA-A47) with downregulation upon stimulation by inflammatory cytokines in chondrocytes. Hattori, T., Kubota, S., Yutani, Y., Fujisawa, T., Nakanishi, T., Takahashi, K., Takigawa, M. J. Cell. Physiol. (2001) [Pubmed]
  21. Structural analysis of the regulatory elements of the type-II procollagen gene. Conservation of promoter and first intron sequences between human and mouse. Vikkula, M., Metsäranta, M., Syvänen, A.C., Ala-Kokko, L., Vuorio, E., Peltonen, L. Biochem. J. (1992) [Pubmed]
  22. Immortalized human adult articular chondrocytes maintain cartilage-specific phenotype and responses to interleukin-1beta. Robbins, J.R., Thomas, B., Tan, L., Choy, B., Arbiser, J.L., Berenbaum, F., Goldring, M.B. Arthritis Rheum. (2000) [Pubmed]
  23. Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes. Annunen, S., Körkkö, J., Czarny, M., Warman, M.L., Brunner, H.G., Kääriäinen, H., Mulliken, J.B., Tranebjaerg, L., Brooks, D.G., Cox, G.F., Cruysberg, J.R., Curtis, M.A., Davenport, S.L., Friedrich, C.A., Kaitila, I., Krawczynski, M.R., Latos-Bielenska, A., Mukai, S., Olsen, B.R., Shinno, N., Somer, M., Vikkula, M., Zlotogora, J., Prockop, D.J., Ala-Kokko, L. Am. J. Hum. Genet. (1999) [Pubmed]
  24. Characterization of an arginine 789 to cysteine substitution in alpha 1 (II) collagen chains of a patient with spondyloepiphyseal dysplasia. Chan, D., Taylor, T.K., Cole, W.G. J. Biol. Chem. (1993) [Pubmed]
  25. Identification of a stop codon mutation in exon 2 of the collagen 2A1 gene in a large stickler syndrome family. Donoso, L.A., Edwards, A.O., Frost, A.T., Ritter, R., Ahmad, N.N., Vrabec, T., Rogers, J., Meyer, D. Am. J. Ophthalmol. (2002) [Pubmed]
  26. Sp1 and Sp3 transcription factors mediate interleukin-1 beta down-regulation of human type II collagen gene expression in articular chondrocytes. Chadjichristos, C., Ghayor, C., Kypriotou, M., Martin, G., Renard, E., Ala-Kokko, L., Suske, G., de Crombrugghe, B., Pujol, J.P., Galéra, P. J. Biol. Chem. (2003) [Pubmed]
  27. Down-regulation of human type II collagen gene expression by transforming growth factor-beta 1 (TGF-beta 1) in articular chondrocytes involves SP3/SP1 ratio. Chadjichristos, C., Ghayor, C., Herrouin, J.F., Ala-Kokko, L., Suske, G., Pujol, J.P., Galéra, P. J. Biol. Chem. (2002) [Pubmed]
  28. A 1.9-Kb 5' fragment from the human COL1A1 gene drives inappropriate expression of the human COL2A1 gene in tissues of transgenic mice that normally express only the COL1A1 gene. Ala-Kokko, L., Yuan, C.M., Le Guellec, D., Franc, S., Fertala, A., Khillan, J.S., Sokolov, B.P., Prockop, D.J. Ann. N. Y. Acad. Sci. (1996) [Pubmed]
  29. Upstream elements present in the 3'-untranslated region of collagen genes influence the processing efficiency of overlapping polyadenylation signals. Natalizio, B.J., Muniz, L.C., Arhin, G.K., Wilusz, J., Lutz, C.S. J. Biol. Chem. (2002) [Pubmed]
  30. Extended passaging, but not aldehyde dehydrogenase activity, increases the chondrogenic potential of human adipose-derived adult stem cells. Estes, B.T., Wu, A.W., Storms, R.W., Guilak, F. J. Cell. Physiol. (2006) [Pubmed]
  31. SOX9 expression does not correlate with type II collagen expression in adult articular chondrocytes. Aigner, T., Gebhard, P.M., Schmid, E., Bau, B., Harley, V., Pöschl, E. Matrix Biol. (2003) [Pubmed]
  32. Double heterozygosity for pseudoachondroplasia and spondyloepiphyseal dysplasia congenita. Unger, S., Korkko, J., Krakow, D., Lachman, R.S., Rimoin, D.L., Cohn, D.H. Am. J. Med. Genet. (2001) [Pubmed]
  33. COL2A1 exon 2 mutations: relevance to the Stickler and Wagner syndromes. Richards, A.J., Martin, S., Yates, J.R., Scott, J.D., Baguley, D.M., Pope, F.M., Snead, M.P. The British journal of ophthalmology. (2000) [Pubmed]
  34. An amino acid substitution (Gly853-->Glu) in the collagen alpha 1(II) chain produces hypochondrogenesis. Bogaert, R., Tiller, G.E., Weis, M.A., Gruber, H.E., Rimoin, D.L., Cohn, D.H., Eyre, D.R. J. Biol. Chem. (1992) [Pubmed]
  35. Differential allelic expression of the type II collagen gene (COL2A1) in osteoarthritic cartilage. Loughlin, J., Irven, C., Athanasou, N., Carr, A., Sykes, B. Am. J. Hum. Genet. (1995) [Pubmed]
  36. Familial spondyloepiphyseal dysplasia tarda, brachydactyly, and precocious osteoarthritis associated with an arginine 75-->cysteine mutation in the procollagen type II gene in a kindred of Chiloe Islanders. I. Clinical, radiographic, and pathologic findings. Reginato, A.J., Passano, G.M., Neumann, G., Falasca, G.F., Diaz-Valdez, M., Jimenez, S.A., Williams, C.J. Arthritis Rheum. (1994) [Pubmed]
  37. Population analysis of the collagen type IIalpha1 3' variable number of tandem repeat polymorphism by heteroduplex genotyping. Uitterlinden, A.G., Huang, Q., Pols, H.A., van Leeuwen, J.P. Electrophoresis (1998) [Pubmed]
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