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 differentiation1. Cell-specific and tissue-specific differences in the expression and function of different CCN family members suggest they have non-redundant roles. Using a positional-candidate approach, we found that mutations in the CCN family member WISP3 are associated with the autosomal recessive skeletal disorder progressive pseudorheumatoid dysplasia (PPD; MIM 208230). PPD is an autosomal recessive disorder that may be initially misdiagnosed as juvenile rheumatoid arthritis2,3,4,5. Its population incidence has been estimated at 1 per million in the United Kingdom4, but it is likely to be higher in the Middle East and Gulf States6. Affected individuals are asymptomatic in early childhood2,3. Signs and symptoms of disease typically develop between three and eight years of age. Clinically and radiographically, patients experience continued cartilage loss and destructive bone changes as they age2,3,4,5,6,7, in several instances necessitating joint replacement surgery by the third decade of life. Extraskeletal manifestations have not been reported in PPD. Cartilage appears to be the primary affected tissue, and in one patient, a biopsy of the iliac crest revealed abnormal nests of chondrocytes and loss of normal cell columnar organization in growth zones5. We have identified nine different WISP3 mutations in unrelated, affected individuals, indicating that the gene is essential for normal post-natal skeletal growth and cartilage homeostasis.