Skip to main content
PMC home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 1997 Dec;34(12):1024–1027. doi: 10.1136/jmg.34.12.1024

Genetic linkage analysis of 14 candidate gene loci in a family with autosomal dominant osteoarthritis without dysplasia.

I Meulenbelt 1, C Bijkerk 1, F C Breedveld 1, P E Slagboom 1
PMCID: PMC1051158  PMID: 9429149

Abstract

The role of various gene loci was investigated in a family in which familial osteoarthritis (FOA), with onset at an early age, is transmitted as an autosomal dominant mendelian trait. The absence of clinical and radiographic signs of dysplasia and calcium pyrophosphate deposition disease (CPDD) indicates that the basic disease process in this family is osteoarthritis (OA). Genetic linkage analysis of 14 candidate genes resulted in the exclusion of 10 important genes (COL2A1, COL9A1, COL9A2, COL11A1, COL11A2, COMP, the CPDD region, CRTL-1, CRTM, and MMP3). Other relevant genes were not informative in this family. The candidate loci previously identified in FOA and heritable skeletal disorders associated with OA are clearly not involved in the development of the primary FOA phenotype in the family investigated, indicating genetic heterogeneity.

Full text

PDF
1024

Images in this article

1025Image
on p.1025
1025Image
on p.1025

Selected References

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

  1. Baldwin C. T., Farrer L. A., Adair R., Dharmavaram R., Jimenez S., Anderson L. Linkage of early-onset osteoarthritis and chondrocalcinosis to human chromosome 8q. Am J Hum Genet. 1995 Mar;56(3):692–697. [PMC free article] [PubMed] [Google Scholar]
  2. Berg E. S., Olaisen B. Characterization of the COL2A1 VNTR polymorphism. Genomics. 1993 May;16(2):350–354. doi: 10.1006/geno.1993.1196. [DOI] [PubMed] [Google Scholar]
  3. Brewton R. G., Wood B. M., Ren Z. X., Gong Y., Tiller G. E., Warman M. L., Lee B., Horton W. A., Olsen B. R., Baker J. R. Molecular cloning of the alpha 3 chain of human type IX collagen: linkage of the gene COL9A3 to chromosome 20q13.3. Genomics. 1995 Nov 20;30(2):329–336. doi: 10.1006/geno.1995.9870. [DOI] [PubMed] [Google Scholar]
  4. Briggs M. D., Choi H., Warman M. L., Loughlin J. A., Wordsworth P., Sykes B. C., Irven C. M., Smith M., Wynne-Davies R., Lipson M. H. Genetic mapping of a locus for multiple epiphyseal dysplasia (EDM2) to a region of chromosome 1 containing a type IX collagen gene. Am J Hum Genet. 1994 Oct;55(4):678–684. [PMC free article] [PubMed] [Google Scholar]
  5. Briggs M. D., Cohn D. H. Length polymorphism within a complex dinucleotide repeat in the human decorin (DCN) gene. Hum Mol Genet. 1993 Jul;2(7):1087–1087. doi: 10.1093/hmg/2.7.1087-a. [DOI] [PubMed] [Google Scholar]
  6. Briggs M. D., Hoffman S. M., King L. M., Olsen A. S., Mohrenweiser H., Leroy J. G., Mortier G. R., Rimoin D. L., Lachman R. S., Gaines E. S. Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nat Genet. 1995 Jul;10(3):330–336. doi: 10.1038/ng0795-330. [DOI] [PubMed] [Google Scholar]
  7. Brunner H. G., van Beersum S. E., Warman M. L., Olsen B. R., Ropers H. H., Mariman E. C. A Stickler syndrome gene is linked to chromosome 6 near the COL11A2 gene. Hum Mol Genet. 1994 Sep;3(9):1561–1564. doi: 10.1093/hmg/3.9.1561. [DOI] [PubMed] [Google Scholar]
  8. Cohn D. H., Briggs M. D., King L. M., Rimoin D. L., Wilcox W. R., Lachman R. S., Knowlton R. G. Mutations in the cartilage oligomeric matrix protein (COMP) gene in pseudoachondroplasia and multiple epiphyseal dysplasia. Ann N Y Acad Sci. 1996 Jun 8;785:188–194. doi: 10.1111/j.1749-6632.1996.tb56258.x. [DOI] [PubMed] [Google Scholar]
  9. Csiszar K., Mariani T. J., Gosin J. S., Deak S. B., Boyd C. D. A restriction fragment length polymorphism results in a nonconservative amino acid substitution encoded within the first exon of the human lysyl oxidase gene. Genomics. 1993 May;16(2):401–406. doi: 10.1006/geno.1993.1203. [DOI] [PubMed] [Google Scholar]
  10. Fässler R., Schnegelsberg P. N., 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 Natl Acad Sci U S A. 1994 May 24;91(11):5070–5074. doi: 10.1073/pnas.91.11.5070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gyapay G., Morissette J., Vignal A., Dib C., Fizames C., Millasseau P., Marc S., Bernardi G., Lathrop M., Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994 Jun;7(2 Spec No):246–339. doi: 10.1038/ng0694supp-246. [DOI] [PubMed] [Google Scholar]
  12. Hanson I. M., Gorman P., Lui V. C., Cheah K. S., Solomon E., Trowsdale J. The human alpha 2(XI) collagen gene (COL11A2) maps to the centromeric border of the major histocompatibility complex on chromosome 6. Genomics. 1989 Nov;5(4):925–931. doi: 10.1016/0888-7543(89)90135-3. [DOI] [PubMed] [Google Scholar]
  13. Hecht J. T., Wang Y., Rhodes C., Yamada Y. GT repeat polymorphism in the human proteoglycan link gene (CRTL1) promoter region. Nucleic Acids Res. 1991 Dec 11;19(23):6666–6666. [PMC free article] [PubMed] [Google Scholar]
  14. Heikkinen J., Hautala T., Kivirikko K. I., Myllylä R. Structure and expression of the human lysyl hydroxylase gene (PLOD): introns 9 and 16 contain Alu sequences at the sites of recombination in Ehlers-Danlos syndrome type VI patients. Genomics. 1994 Dec;24(3):464–471. doi: 10.1006/geno.1994.1654. [DOI] [PubMed] [Google Scholar]
  15. Hellsten E., Vesa J., Heiskanen M., Mäkelä T. P., Järvelä I., Cowell J. K., Mead S., Alitalo K., Palotie A., Peltonen L. Identification of YAC clones for human chromosome 1p32 and physical mapping of the infantile neuronal ceroid lipofuscinosis (INCL) locus. Genomics. 1995 Jan 20;25(2):404–412. doi: 10.1016/0888-7543(95)80040-s. [DOI] [PubMed] [Google Scholar]
  16. Hyland J., Ala-Kokko L., Royce P., Steinmann B., Kivirikko K. I., Myllylä R. A homozygous stop codon in the lysyl hydroxylase gene in two siblings with Ehlers-Danlos syndrome type VI. Nat Genet. 1992 Nov;2(3):228–231. doi: 10.1038/ng1192-228. [DOI] [PubMed] [Google Scholar]
  17. Kuivaniemi H., Peltonen L., Kivirikko K. I. Type IX Ehlers-Danlos syndrome and Menkes syndrome: the decrease in lysyl oxidase activity is associated with a corresponding deficiency in the enzyme protein. Am J Hum Genet. 1985 Jul;37(4):798–808. [PMC free article] [PubMed] [Google Scholar]
  18. Lathrop G. M., Lalouel J. M., Julier C., Ott J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am J Hum Genet. 1985 May;37(3):482–498. [PMC free article] [PubMed] [Google Scholar]
  19. Li Y., Lacerda D. A., Warman M. L., Beier D. R., Yoshioka H., Ninomiya Y., Oxford J. T., Morris N. P., Andrikopoulos K., Ramirez F. A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis. Cell. 1995 Feb 10;80(3):423–430. doi: 10.1016/0092-8674(95)90492-1. [DOI] [PubMed] [Google Scholar]
  20. Litt M., Sharma V., Luty J. A. Dinucleotide repeat polymorphism at the D11S35 locus. Nucleic Acids Res. 1990 Oct 11;18(19):5921–5921. doi: 10.1093/nar/18.19.5921-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Martin M., Mann D., Carrington M. Recombination rates across the HLA complex: use of microsatellites as a rapid screen for recombinant chromosomes. Hum Mol Genet. 1995 Mar;4(3):423–428. doi: 10.1093/hmg/4.3.423. [DOI] [PubMed] [Google Scholar]
  22. Meulenbelt I., Droog S., Trommelen G. J., Boomsma D. I., Slagboom P. E. High-yield noninvasive human genomic DNA isolation method for genetic studies in geographically dispersed families and populations. Am J Hum Genet. 1995 Nov;57(5):1252–1254. [PMC free article] [PubMed] [Google Scholar]
  23. Muragaki Y., Mariman E. C., van Beersum S. E., Perälä M., van Mourik J. B., Warman M. L., Olsen B. R., Hamel B. C. A mutation in the gene encoding the alpha 2 chain of the fibril-associated collagen IX, COL9A2, causes multiple epiphyseal dysplasia (EDM2). Nat Genet. 1996 Jan;12(1):103–105. doi: 10.1038/ng0196-103. [DOI] [PubMed] [Google Scholar]
  24. Mäkelä T. P., Hellsten E., Vesa J., Alitalo K., Peltonen L. An Alu variable polyA repeat polymorphism upstream of L-myc at 1p32. Hum Mol Genet. 1992 Jun;1(3):217–217. doi: 10.1093/hmg/1.3.217-a. [DOI] [PubMed] [Google Scholar]
  25. 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 Natl Acad Sci U S A. 1993 Apr 1;90(7):2870–2874. doi: 10.1073/pnas.90.7.2870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nedospasov S. A., Udalova I. A., Kuprash D. V., Turetskaya R. L. DNA sequence polymorphism at the human tumor necrosis factor (TNF) locus. Numerous TNF/lymphotoxin alleles tagged by two closely linked microsatellites in the upstream region of the lymphotoxin (TNF-beta) gene. J Immunol. 1991 Aug 1;147(3):1053–1059. [PubMed] [Google Scholar]
  27. 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]
  28. Patel M. S., Mankoo B. S., Brickell P. M. A polymorphic microsatellite repeat is located close to the promoter region of the c-fgr proto-oncogene (FGR) at chromosome 1p36.2-p36.1. Hum Mol Genet. 1992 Apr;1(1):65–65. doi: 10.1093/hmg/1.1.65-a. [DOI] [PubMed] [Google Scholar]
  29. Prockop D. J., Kivirikko K. I. Collagens: molecular biology, diseases, and potentials for therapy. Annu Rev Biochem. 1995;64:403–434. doi: 10.1146/annurev.bi.64.070195.002155. [DOI] [PubMed] [Google Scholar]
  30. Pun Y. L., Moskowitz R. W., Lie S., Sundstrom W. R., Block S. R., McEwen C., Williams H. J., Bleasel J. F., Holderbaum D., Haqqi T. M. Clinical correlations of osteoarthritis associated with a single-base mutation (arginine519 to cysteine) in type II procollagen gene. A newly defined pathogenesis. Arthritis Rheum. 1994 Feb;37(2):264–269. doi: 10.1002/art.1780370216. [DOI] [PubMed] [Google Scholar]
  31. Richards A. J., Yates J. R., Williams R., Payne S. J., Pope F. M., Scott J. D., Snead M. P. A family with Stickler syndrome type 2 has a mutation in the COL11A1 gene resulting in the substitution of glycine 97 by valine in alpha 1 (XI) collagen. Hum Mol Genet. 1996 Sep;5(9):1339–1343. doi: 10.1093/hmg/5.9.1339. [DOI] [PubMed] [Google Scholar]
  32. Ritvaniemi P., Körkkö J., Bonaventure J., Vikkula M., Hyland J., Paassilta P., Kaitila I., Käriäinen H., Sokolov B. P., Hakala M. Identification of COL2A1 gene mutations in patients with chondrodysplasias and familial osteoarthritis. Arthritis Rheum. 1995 Jul;38(7):999–1004. doi: 10.1002/art.1780380717. [DOI] [PubMed] [Google Scholar]
  33. Steinlein O., Fischer C., Keil R., Smigrodzki R., Vogel F. D20S19, linked to low voltage EEG, benign neonatal convulsions, and Fanconi anaemia, maps to a region of enhanced recombination and is localized between CpG islands. Hum Mol Genet. 1992 Aug;1(5):325–329. doi: 10.1093/hmg/1.5.325. [DOI] [PubMed] [Google Scholar]
  34. Vikkula M., Mariman E. C., Lui V. C., Zhidkova N. I., Tiller G. E., Goldring M. B., van Beersum S. E., de Waal Malefijt M. C., van den Hoogen F. H., Ropers H. H. Autosomal dominant and recessive osteochondrodysplasias associated with the COL11A2 locus. Cell. 1995 Feb 10;80(3):431–437. doi: 10.1016/0092-8674(95)90493-x. [DOI] [PubMed] [Google Scholar]
  35. 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]
  36. Wang Y., Sadler L., Hecht J. T. Polymorphic dinucleotide repeat in a cartilage matrix protein (CRTM) gene. Hum Mol Genet. 1992 Dec;1(9):780–780. doi: 10.1093/hmg/1.9.780-a. [DOI] [PubMed] [Google Scholar]
  37. Warman M. L., Tiller G. E., Polumbo P. A., Seldin M. F., Rochelle J. M., Knoll J. H., 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. 1993 Sep;17(3):694–698. doi: 10.1006/geno.1993.1391. [DOI] [PubMed] [Google Scholar]
  38. Williams C. J., Jimenez S. A. Heritable diseases of cartilage caused by mutations in collagen genes. J Rheumatol Suppl. 1995 Feb;43:28–33. [PubMed] [Google Scholar]
  39. Williams C. J., Rock M., Considine E., McCarron S., Gow P., Ladda R., McLain D., Michels V. M., Murphy W., Prockop D. J. Three new point mutations in type II procollagen (COL2A1) and identification of a fourth family with the COL2A1 Arg519-->Cys base substitution using conformation sensitive gel electrophoresis. Hum Mol Genet. 1995 Feb;4(2):309–312. doi: 10.1093/hmg/4.2.309. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES