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Pseudoachondroplasia and multiple epiphyseal dysplasia: New etiologic developments

Authors

  • Sheila Unger,

    Corresponding author
    • Division of Clinical and Metabolic Genetics, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8.
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    • Sheila Unger is a staff geneticist in the Division of Clinical and Metabolic Genetics at the Hospital for Sick Children in Toronto and an Assistant Professor of Paediatrics at the University of Toronto. She is board certified in medical genetics in both Canada and the United States and has an interest in the skeletal dysplasias and related disorders.

  • Jacqueline T. Hecht

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    • Jacqueline Hecht is a researcher in the Division of Medical Genetics at the Department of Pediatrics, University of Texas Houston Medical School. A focus of her research has been to identify the genetic mechanisms causing pseudoachondroplasia. Towards this goal, her team has identified that mutations in cartilage oligomeric matric protein cause this condition. Biochemical and cellular analyses have demonstrated that the mutations affect the protein conformation and that the protein changes are recognized by protein chaperones which retain the unprocessed COMP protein.


Abstract

Pseudoachondroplasia (PSACH) (OMIM#177170) and multiple epiphyseal dysplasia (MED) are separate but overlapping osteochondrodysplasias. PSACH is a dominantly inherited disorder characterized by short-limb short stature, loose joints, and early-onset osteoarthropathy. The diagnosis is based on characteristic clinical and radiographic findings. Only mutations in the cartilage oligomeric matrix protein (COMP) gene have been reported in PSACH, and all family studies have been consistent with linkage to the COMP locus on chromosome 19. Multiple epiphyseal dysplasia (MED) is a relatively mild chondrodysplasia but like PSACH, MED causes early-onset joint degeneration, particularly of the large weight-bearing joints. Given the clinical similarity between PSACH and MED, it was not surprising that the first MED locus identified was the COMP gene (EDM1). Mutations causing MED have now been identified in five other genes (COL9A1, COL9A2, COL9A3, DTDST, and MATN3), making MED one of the most genetically heterogeneous disorders. This article reviews the clinical features of PSACH and MED, the known mutations, and the pathogenetic effect of COMP mutations on the cartilage extracellular matrix. © 2002 Wiley-Liss, Inc.

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