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. 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 arthritis. Its population incidence has been estimated at 1 per million in the United Kingdom, but it is likely to be higher in the Middle East and Gulf States. Affected individuals are asymptomatic in early childhood. 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 age, 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 zones. 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.

Fine mapping of progressive pseudorheumatoid dysplasia: a tool for heterozygote identification.

Progressive pseudorheumatoid dysplasia is a skeletal genetic disorder affecting primarily the articular cartilage, causing joint stiffness and leading to a crippling status. More than two-thirds of the reported patients belong to Arab and Mediterranean populations. The disease locus has been mapped to chromosome 6q22 in a region of 12.9 cM using a Jordanian family. We examined two additional families, one Jordanian and one Palestinian, to test for homogeneity of the disorder and the presence of a common haplotype, to fine map the disorder, and to use all the information to derive a tool for heterozygote identification. The two families showed linkage to the same previously reported locus, thus suggesting homogeneity, but they did not share a common haplotype. They also provided information that refined the genetic region for the disease locus to 2.1 cM with three microsatellite markers. The absence of a common haplotype indicates that no common ancestor mutations were inherited by our patients. Genotyping for the three-marker haplotype showed that it can be used as a heterozygote identification tool.

Assignment of gene responsible for progressive pseudorheumatoid dysplasia to chromosome 6 and examination of COL10A1 as candidate gene.

Progressive pseudorheumatoid dysplasia is an autosomal recessive skeletal dysplasia with radiographic changes in the spine similar to Spondyleopiphyseal dysplasia tarda and clinical, though not radiographic resemblance to rheumatoid arthritis. About two-thirds of the reported patients are of Arabic and Mediterranean origin which reflects the relative high incidence in this population. We performed homozygosity mapping utilising the DNA pooling approach to map progressive pseudorheumatoid dysplasia to a chromosomal region on the long arm of chromosome 6. We examined a possible candidate gene in the same region of linkage, namely COL10A1, for alterations in this disorder. We did not identify any mutations in our family, but did not totally exclude COL10A1 gene from being the disease-causing gene.