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. 1995 May;56(5):1186–1193.

Differential allelic expression of the type II collagen gene (COL2A1) in osteoarthritic cartilage.

J Loughlin 1, C Irven 1, N Athanasou 1, A Carr 1, B Sykes 1
PMCID: PMC1801477  PMID: 7726176

Abstract

Osteoarthritis (OA) is a common debilitating disease resulting from the degeneration of articular cartilage. The major protein of cartilage is type II collagen, which is encoded by the COL2A1 gene. Mutations at this locus have been discovered in several individuals with inherited disorders of cartilage. We have identified 27 primary OA patients who are heterozygous for sequence dimorphisms located in the coding region of COL2A1. These dimorphisms were used to distinguish the mRNA output from each of the two COL2A1 alleles in articular cartilage obtained from each patient. Three patients demonstrated differential allelic expression and produced < 12% of the normal level of mRNA from one of their COL2A1 alleles. 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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahmad N. N., Ala-Kokko L., Knowlton R. G., Jimenez S. A., Weaver E. J., Maguire J. I., Tasman W., Prockop D. J. Stop codon in the procollagen II gene (COL2A1) in a family with the Stickler syndrome (arthro-ophthalmopathy). Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6624–6627. doi: 10.1073/pnas.88.15.6624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ahmad N. N., McDonald-McGinn D. M., Zackai E. H., Knowlton R. G., LaRossa D., DiMascio J., Prockop D. J. A second mutation in the type II procollagen gene (COL2AI) causing stickler syndrome (arthro-ophthalmopathy) is also a premature termination codon. Am J Hum Genet. 1993 Jan;52(1):39–45. [PMC free article] [PubMed] [Google Scholar]
  3. Aigner T., Stöss H., Weseloh G., Zeiler G., von der Mark K. Activation of collagen type II expression in osteoarthritic and rheumatoid cartilage. Virchows Arch B Cell Pathol Incl Mol Pathol. 1992;62(6):337–345. doi: 10.1007/BF02899701. [DOI] [PubMed] [Google Scholar]
  4. Ala-Kokko L., Baldwin C. T., Moskowitz R. W., Prockop D. J. Single base mutation in the type II procollagen gene (COL2A1) as a cause of primary osteoarthritis associated with a mild chondrodysplasia. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6565–6568. doi: 10.1073/pnas.87.17.6565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Baldwin C. T., Reginato A. M., Smith C., Jimenez S. A., Prockop D. J. Structure of cDNA clones coding for human type II procollagen. The alpha 1(II) chain is more similar to the alpha 1(I) chain than two other alpha chains of fibrillar collagens. Biochem J. 1989 Sep 1;262(2):521–528. doi: 10.1042/bj2620521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Beighton P., De Paepe A., Hall J. G., Hollister D. W., Pope F. M., Pyeritz R. E., Steinmann B., Tsipouras P. Molecular nosology of heritable disorders of connective tissue. Am J Med Genet. 1992 Feb 15;42(4):431–448. doi: 10.1002/ajmg.1320420406. [DOI] [PubMed] [Google Scholar]
  7. Brown D. M., Nichols B. E., Weingeist T. A., Sheffield V. C., Kimura A. E., Stone E. M. Procollagen II gene mutation in Stickler syndrome. Arch Ophthalmol. 1992 Nov;110(11):1589–1593. doi: 10.1001/archopht.1992.01080230089027. [DOI] [PubMed] [Google Scholar]
  8. Cheah K. S., Stoker N. G., Griffin J. R., Grosveld F. G., Solomon E. Identification and characterization of the human type II collagen gene (COL2A1). Proc Natl Acad Sci U S A. 1985 May;82(9):2555–2559. doi: 10.1073/pnas.82.9.2555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  10. Dietz H. C., McIntosh I., Sakai L. Y., Corson G. M., Chalberg S. C., Pyeritz R. E., Francomano C. A. Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome. Genomics. 1993 Aug;17(2):468–475. doi: 10.1006/geno.1993.1349. [DOI] [PubMed] [Google Scholar]
  11. Hewett D., Lynch J., Child A., Firth H., Sykes B. Differential allelic expression of a fibrillin gene (FBN1) in patients with Marfan syndrome. Am J Hum Genet. 1994 Sep;55(3):447–452. [PMC free article] [PubMed] [Google Scholar]
  12. Horton W. E., Jr, Wang L., Bradham D., Precht P., Balakir R. The control of expression of type II collagen: relevance to cartilage disease. DNA Cell Biol. 1992 Apr;11(3):193–198. doi: 10.1089/dna.1992.11.193. [DOI] [PubMed] [Google Scholar]
  13. Hull R., Pope F. M. Osteoarthritis and cartilage collagen genes. Lancet. 1989 Jun 10;1(8650):1337–1338. doi: 10.1016/s0140-6736(89)92741-4. [DOI] [PubMed] [Google Scholar]
  14. Hultman T., Ståhl S., Hornes E., Uhlén M. Direct solid phase sequencing of genomic and plasmid DNA using magnetic beads as solid support. Nucleic Acids Res. 1989 Jul 11;17(13):4937–4946. doi: 10.1093/nar/17.13.4937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. KELLGREN J. H., LAWRENCE J. S., BIER F. GENETIC FACTORS IN GENERALIZED OSTEO-ARTHROSIS. Ann Rheum Dis. 1963 Jul;22:237–255. doi: 10.1136/ard.22.4.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Knowlton R. G., Katzenstein P. L., Moskowitz R. W., Weaver E. J., Malemud C. J., Pathria M. N., Jimenez S. A., Prockop D. J. Genetic linkage of a polymorphism in the type II procollagen gene (COL2A1) to primary osteoarthritis associated with mild chondrodysplasia. N Engl J Med. 1990 Feb 22;322(8):526–530. doi: 10.1056/NEJM199002223220807. [DOI] [PubMed] [Google Scholar]
  17. Lee B., Vissing H., Ramirez F., Rogers D., Rimoin D. Identification of the molecular defect in a family with spondyloepiphyseal dysplasia. Science. 1989 May 26;244(4907):978–980. doi: 10.1126/science.2543071. [DOI] [PubMed] [Google Scholar]
  18. Loughlin J., Irven C., Fergusson C., Sykes B. Sibling pair analysis shows no linkage of generalized osteoarthritis to the loci encoding type II collagen, cartilage link protein or cartilage matrix protein. Br J Rheumatol. 1994 Dec;33(12):1103–1106. doi: 10.1093/rheumatology/33.12.1103. [DOI] [PubMed] [Google Scholar]
  19. Palotie A., Väisänen P., Ott J., Ryhänen L., Elima K., Vikkula M., Cheah K., Vuorio E., Peltonen L. Predisposition to familial osteoarthrosis linked to type II collagen gene. Lancet. 1989 Apr 29;1(8644):924–927. doi: 10.1016/s0140-6736(89)92507-5. [DOI] [PubMed] [Google Scholar]
  20. Priestley L., Fergusson C., Ogilvie D., Wordsworth P., Smith R., Pattrick M., Doherty M., Sykes B. A limited association of generalized osteoarthritis with alleles at the type II collagen locus: COL2A1. Br J Rheumatol. 1991 Aug;30(4):272–275. doi: 10.1093/rheumatology/30.4.272. [DOI] [PubMed] [Google Scholar]
  21. Ritvaniemi P., Hyland J., Ignatius J., Kivirikko K. I., Prockop D. J., Ala-Kokko L. A fourth example suggests that premature termination codons in the COL2A1 gene are a common cause of the Stickler syndrome: analysis of the COL2A1 gene by denaturing gradient gel electrophoresis. Genomics. 1993 Jul;17(1):218–221. doi: 10.1006/geno.1993.1306. [DOI] [PubMed] [Google Scholar]
  22. Ritvaniemi P., Sokolov B. P., Williams C. J., Considine E., Yurgenev L., Meerson E. M., Ala-Kokko L., Prockop D. J. 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. Hum Mutat. 1994;3(3):261–267. doi: 10.1002/humu.1380030314. [DOI] [PubMed] [Google Scholar]
  23. Ryan M. C., Sieraski M., Sandell L. J. The human type II procollagen gene: identification of an additional protein-coding domain and location of potential regulatory sequences in the promoter and first intron. Genomics. 1990 Sep;8(1):41–48. doi: 10.1016/0888-7543(90)90224-i. [DOI] [PubMed] [Google Scholar]
  24. Stacey A., Bateman J., Choi T., Mascara T., Cole W., Jaenisch R. Perinatal lethal osteogenesis imperfecta in transgenic mice bearing an engineered mutant pro-alpha 1(I) collagen gene. Nature. 1988 Mar 10;332(6160):131–136. doi: 10.1038/332131a0. [DOI] [PubMed] [Google Scholar]
  25. Vikkula M., Nissilä M., Hirvensalo E., Nuotio P., Palotie A., Aho K., Peltonen L. Multiallelic polymorphism of the cartilage collagen gene: no association with osteoarthrosis. Ann Rheum Dis. 1993 Oct;52(10):762–764. doi: 10.1136/ard.52.10.762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Vikkula M., Palotie A., Ritvaniemi P., Ott J., Ala-Kokko L., Sievers U., Aho K., Peltonen L. Early-onset osteoarthritis linked to the type II procollagen gene. Detailed clinical phenotype and further analyses of the gene. Arthritis Rheum. 1993 Mar;36(3):401–409. doi: 10.1002/art.1780360317. [DOI] [PubMed] [Google Scholar]
  27. Vissing H., Rasmussen M., D'Alessio M., Lee B., Dobkin C., Ramirez F. A glycine to serine polymorphism in the C-propeptide of the human type II procollagen. Nucleic Acids Res. 1990 Jun 11;18(11):3431–3431. doi: 10.1093/nar/18.11.3431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Williams C. J., Harrison D. A., Hopkinson I., Baldwin C. T., Ahmad N. N., Ala-Kokko L., Korn R. M., Buxton P. G., Dimascio J., Considine E. L. Detection of sequence variants in the gene for human type II procollagen (COL2A1) by direct sequencing of polymerase chain reaction-amplified genomic DNA. Hum Mutat. 1992;1(5):403–416. doi: 10.1002/humu.1380010510. [DOI] [PubMed] [Google Scholar]
  29. Willing M. C., Deschenes S. P., Scott D. A., Byers P. H., Slayton R. L., Pitts S. H., Arikat H., Roberts E. J. Osteogenesis imperfecta type I: molecular heterogeneity for COL1A1 null alleles of type I collagen. Am J Hum Genet. 1994 Oct;55(4):638–647. [PMC free article] [PubMed] [Google Scholar]
  30. Willing M. C., Pruchno C. J., Atkinson M., Byers P. H. Osteogenesis imperfecta type I is commonly due to a COL1A1 null allele of type I collagen. Am J Hum Genet. 1992 Sep;51(3):508–515. [PMC free article] [PubMed] [Google Scholar]

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