Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia

Members of the CCN (for CTGF; cyr61/cef10, nov) gene family encode cysteine -rich secreted proteins with roles in cell growth and differentiation(1). C ell-specific and tissue-specific differences in the expression and function of different CCN family members suggest they have non-redundant roles. Usi ng a positional-candidate approach, we found that mutations in the CCN fami ly member WISP3 are associated with the autosomal recessive skeletal disord er progressive pseudorheumatoid dysplasia (PPD; MIM 208230). PPD is an auto somal recessive disorder that may be initially misdiagnosed as juvenile rhe umatoid arthritis(2-5). Its population incidence has been estimated at 1 pe r million in the United Kingdom(4), but it is likely to be higher in the Mi ddle East and Gulf States(6). Affected individuals are asymptomatic in earl y childhood(2, 3). Signs and symptoms of disease typically develop between three and eight years of age. Clinically and radiographically, patients exp erience continued cartilage loss and destructive bone changes as they age(2 -7), in several instances necessitating joint replacement surgery by the th ird decade of life. Extraskeletal manifestations have not been reported in PPD. Cartilage appears to he the primary affected tissue, and in one patien t, a biopsy of the iliac crest revealed abnormal nests of chondrocytes and loss of normal cell columnar organization in growth zones(5). We have ident ified nine different WISP3 mutations in unrelated, affected individuals, in dicating that the gene is essential for normal post-natal skeletal growth a nd cartilage homeostasis.