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.
Hurvitz
J R
JR
Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
Suwairi
W M
WM
Van Hul
W
W
El-Shanti
H
H
Superti-Furga
A
A
Roudier
J
J
Holderbaum
D
D
Pauli
R M
RM
Herd
J K
JK
Van Hul
E V
EV
Rezai-Delui
H
H
Legius
E
E
Le Merrer
M
M
Al-Alami
J
J
Bahabri
S A
SA
Warman
M L
ML
D000293:Adolescent; D001842:Bone and Bones / Q000502:physiology; D055511:CCN Intercellular Signaling Proteins; D002356:Cartilage / Q000254:growth & development / Q000502:physiology; D002896:Chromosomes, Human, Pair 6; D055513:Connective Tissue Growth Factor; D006133:Growth Substances / Q000235:genetics*; D006225:Hand / Q000000981:diagnostic imaging; D006239:Haplotypes; D006801:Humans; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D055514:Nephroblastoma Overexpressed Protein; D015513:Oncogene Proteins; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000235:genetics*; D011518:Proto-Oncogene Proteins; D011859:Radiography
D055511:CCN Intercellular Signaling Proteins; C526317:CCN2 protein, human; C526319:CCN3 protein, human; C116396:CCN4 protein, human; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D055514:Nephroblastoma Overexpressed Protein; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D055513:Connective Tissue Growth Factor