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

Abstract

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.

A novel variant of WISP1 lacking a Von Willebrand type C module overexpressed in scirrhous gastric carcinoma

“…Kumar et al (1999) reported that WISP2 is a secreted protein which positively regulates osteoblast functions. Unlike all other known CCN proteins, four of 10 conserved cysteine residues are not recognized in the VWC module of WISP3 that is frequently mutated in patients with progressive pseudorheumatoid dysplasia (Hurvitz et al, 1999). In our experiments, WISP1v lacking the second module of VWC induced a striking cellular transformation and a rapid piling-up forms of growth.…”

WISP3‐dependent regulation of type II collagen and aggrecan production in chondrocytes

“…WISP3 mutations have been linked to an autosomal-recessive skeletal disorder, progressive pseudorheumatoid dysplasia (PPRD), that is marked by abnormal skeletal growth and progressive cartilage loss (10,11). The identification of 9 independent WISP3 mutations in unrelated PPRD patients suggests that WISP3 mutations might play an important role in the development of PPRD.…”

“…tine (1,10). Like other CCN family members, WISP3 encodes several potentially functional domains, each domain corresponding roughly to 1 exon (3,4,10).…”

“…Like other CCN family members, WISP3 encodes several potentially functional domains, each domain corresponding roughly to 1 exon (3,4,10). Exon 1 encodes a peptide signal sequence, exon 2 encodes a domain that bears homology to the amino-terminal domain of the insulin-like growth factor binding proteins (IGFBPs), exon 3 encodes a von Willebrand factor type C repeat domain that may participate in peptide oligomerization, exon 4 encodes a thrombospondin type 1 domain that may bind to sulfated glycosaminoglycans, and exon 5 encodes a cysteine knot domain that may be involved in dimerization and receptor binding.…”

A genotyping assay for missense mutation in WISP3 gene associated with childhood onset pseudorheumatoid arthropathy

“…WISP3 gene spans over 5 exons and encodes several functional domains each corresponding to one of the exons. Exon 1 encodes a peptide sequence that plays role in Wisp secretion (7,(10)(11)(12); exon 2 codes for insulin-like growth factor binding proteins (IGFBPs) that contains twelve cysteine residues (7,10,12-15); exon 3 encodes a cysteine rich, von Willebrand factor type C repeat domain (10,11,13,15); exon 4 contains information for a thrombospondin type 1 domain biosynthesis (with six cysteine residues) that may bind to sulfated glycosaminoglycan's either at cell surfaces or in extracellular matrix (11,12,(15)(16)(17)(18); and exon 5 that encodes a cysteine knot domain comprised of ten cysteine residues possibly involved in dimerization and receptor binding (10)(11)(12)(14)(15)(16)(17)(19)(20)(21)(22)(23)(24). Until now, a number of mutations and polymorphisms were found throughout the WISP3 sequence with geographically localized origin ( Table 2).…”