Abstract
Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are dominantly inherited chondrodysplasias characterized by short stature and early–onset osteoarthrosis. The disease genes in families with PSACH and MED have been localized to an 800 kilobase interval on the short arm of chromosome 19. Recently the gene for cartilage oligomeric matrix protein (COMP) was localized to chromosome 19p13.1. In three patients with these diseases, we identified COMP mutations in a region of the gene that encodes a Ca++ binding motif. Our data demonstrate that PSACH and some forms of MED are allelic and suggest an essential role for Ca++ binding in COMP structure and function.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
International Working Group on Constitutional Diseases of Bone. International classification of osteochondrodysplasias. Am. J. med. Genet. 44, 223–229 (1992).
Maroteaux, P., Stanescu, R., Stanescu, V. & Fontaine, G. The mild form of pseudoachondroplasia. Eur. J. Pediatr. 133, 227–231 (1980).
Rimoin, D.L. et al. A large family with features of pseudoachondroplasia and multiple epiphyseal dysplasia: exclusion of seven candidate gene loci that encode proteins of the cartilage extracellular matrix. Hum. Genet. 93, 236–242 (1994).
Ribbing, S. Studien über hereditäre multiple Epiphysenstörungen. Acta. Radiol. Suppl. 34, 1–107 (1937).
Maroteaux, P. & Lamy, M. Les formes pseudoachondroplastiques des dysplasies spondylo-epiphysaires. Presse Med. 67, 383–386 (1959).
Fairbank, T. Dysplasia epiphysialis multiplex. Br. J. Surg. 34, 225–232 (1947).
Maynard, J.A., Cooper, R.R. & Ponseti, I.V. A unique rough surfaced endoplasmic reticulum inclusion in pseudoachondroplasia. Lab. Invest. 26, 40–44 (1972).
Stanescu, V., Stanescu, R. & Maroteaux, P. Etude morphologique et biochimique du cartilage de croissance dans les osteochondrodysplasies. Arch. Franc. Pediatr. 34, 1–80 (1977).
Stanescu, R., Stanescu, V., Muriel, M.P. & Maroteaux, P. Multiple epiphyseal dysplasia, Fairbank type: Morphologic and biochemical study of cartilage. Am. J. med. Genet. 45, 501–507 (1993).
Stanescu, V., Maroteaux, P. & Stanescu, R. The biochemical defect of pseudoachondroplasia. Eur. J. Pediatr. 138, 221–225 (1982).
Briggs, M.D. et al. Genetic linkage of pseudoachondroplasia to markers in the pericentromeric region of chromosome 19. Genomics. 18, 656–660 (1993).
Hecht, J.T. et al. Linkage of typical pseudoachondroplasia to chromosome 19. Genomics 18, 661–666 (1993).
Oehlmann, R., Summerville, G.P., Yeh, G., Weaver, E.J., Jiminez, S.A. & Knowlton, R.G. Genetic linkage mapping of multiple epiphyseal dysplasia to the pericentromeric region of chromosome 19. Am. J. hum. Genet. 54, 3–10 (1994).
Briggs, M.D. et al. 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. 55, 678–684 (1994).
Warman, M.L. et al. The genes encoding a2(IX) collagen (COL9A2) map to human chromosome 1 p32.2–p33 and mouse chromosome 4. Genomics 23, 158–162 (1994).
Hellsten, E. et al. Identification of YAC clones for human chromosome 1 p32 and physical mapping of the infantile neuronal ceroid lipofuscinosos (INCL) locus. Genomics 25, 404–412 (1995).
Deere, M. et al. Genetic heterogeneity in multiple epiphyseal dysplasia. Am. J. hum. Genet.. 56, 698–704 (1995).
Knowlton, R.G. et al. High resolution genetic and physical mapping of multiple epiphyseal dysplasia and pseudoachondroplasia mutations at chromosome 19p13.1–p12. Genomics. (in the press).
Hedbom, E. et al. Cartilage matrix proteins. J. biol. Chem. 267, 6132–6136 (1992).
Newton, G. et al. Characterization of human and mouse cartilage oligomeric matrix protein. Genomics 24, 435–439 (1994).
Tynan, K. et al. Organization of the multiple polymorphic sites of the D19S11 locus within a 650-kb cosmid contig. Genomics 17, 316–323 (1993).
Brandriff, B.F. et al. Human chromosome 19p: A fluorescence in situhybridization map with genomic distance estimates for 79 intervals spanning 20Mb. Genomics 23, 582–591 (1994).
Bomstein, P., Devarayalu, S., Edelhoff, S. & Disteche, C.M. Isolation and characterization of the mouse thrombospondins (Thbs3) gene. Genomics 15, 607–613 (1993).
Lawler, J. & Hynes, R.O. The structure of human thrombospondin, an adhesive glycoprotein with multiple calcium-binding sites and homologies with several different proteins. J. Cell Biol. 103, 1635–1648 (1986).
Orita, M., Iwahana, H., Kanazawa, H., Hayashi, K. & Sekiya, T. Detection of polymorphisms of human DMA by gel etectrophoresis as single-stranded conformation polymorphisms. Proc. natn. Acad. Sci. U.S.A. 86, 2766–2770 (1989).
Morgelin, M., Heinegard, D., Engel, J. & Paulsson, M. Electron microscopy of native cartilage oligomeric matrix protein purified from the swarm rat chondrosarcoma reveals a five-armed structure. J. biol. Chem. 267, 6137–6141 (1992).
Oldberg, Å., Antonsson, P., Lindblom, K. & Heinegard, D. COMP (cartilage oligomeric matrix protein) is structurally related to the thrombospondins. J. biol. Chem. 267, 22346–22350 (1992).
Efimov, V.P., Lustig, A. & Engel, J. The thrombospondin-like chains of cartilage oligomeric matrix protein are assembled by a five-stranded a-helical bundle between residues 20 and 83. FEBS Lett. 341, 54–58 (1994).
Bornstein, P. Thrombospondins: structure and regulation of expression. FASEB J. 6, 3290–3299 (1992).
Takagi, J., Fujisawa, T., Usui, T., Aoyoma, T., & Saito, Y. A single chain 19-kDa fragmant from bovine thrombospondin binds to type V collagen and heparin. J. biol. Chem. 268, 15544–15549 (1993).
Mumby, S.M., Raugi, C.J. & Bornstein, P. Interactions of thrombospondin with extracellular matrix proteins: selective binding to type V collagen. J. Cell Biol. 98, 646–652 (1984).
Lahav, J., Schwartz, M.A. & Hynes, R.O. Analysis of platelet adhesion with a radioactive chemical crosslinking reagent: interaction of thrombospondin with flbronectin and collagen. Cell 31, 253–262 (1982).
Dixit, V.M., Hennessy, S.W., Grant, G.A., Santoro, S.A. & Frazier, W.A. Isolation and characterization of a heparin-binding domain from the amino terminus of platelet thrombospondin. J. biol. Chem. 259, 10100–10105 (1984).
Klee, C.B., Couch, T.H. & Richmond, P.G. Calmodulin. A Rev. Biochem. 49, 489–515 (1980).
DiCesare, P., Hauser. N., Lehman, D., Pasumarti, S. & Paulsson, M. Cartilage oligomeric matrix protein is an abundant component of tendon. FEBS Lett. 354, 237–240 (1994).
Hall, J.G., Dorst, J.P., Rotta, J. & McKusick, V.A. Gonadal mosaicism in pseudoachondroplasia. Am. J. hum. Genet. 28, 143–151 (1987).
Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Muttitocus linkage analysis in humans: detection of linkage and estimation of recombination. Am. J. hum. Genet. 37, 482–498 (1985).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Briggs, M., Hoffman, S., King, L. et al. Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nat Genet 10, 330–336 (1995). https://doi.org/10.1038/ng0795-330
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0795-330
This article is cited by
-
Cartilage oligomeric matrix protein overexpression is an independent poor prognostic indicator in patients with intrahepatic cholangiocarcinoma
Scientific Reports (2023)
-
Clinical, Biochemical, Radiological, Genetic and Therapeutic Analysis of Patients with COMP Gene Variants
Calcified Tissue International (2022)
-
Mutations in COMP cause familial carpal tunnel syndrome
Nature Communications (2020)
-
Direct, gabapentin-insensitive interaction of a soluble form of the calcium channel subunit α2δ-1 with thrombospondin-4
Scientific Reports (2019)
-
Proteins with calmodulin-like domains: structures and functional roles
Cellular and Molecular Life Sciences (2019)