title: Identification of novel mutations in WISP3 gene in two unrelated Chinese families with progressive pseudorheumatoid dysplasia.
abstract: BACKGROUND
  Progressive pseudorheumatoid dysplasia (PPD) is an autosomal recessive genetic disease and it has been reported that PPD is caused by mutations of the Wnt1-inducible signaling pathway protein 3 (WISP3) gene which is located on chromosome 6q22. Up to date, 16 different mutations in the WISP3 have been identified in patients with PPD in different countries previously, but only two mutations in exon 5 were previously identified from Asian origin. Our study aimed to characterize the clinical manifestations and features of PPD and screen the mutations of the disease causing WISP3, and try to elucidate the molecular pathogenesis of PPD.
  
  
  METHODS
  Altogether, 153 persons, including 4 affected individuals, 49 unaffected individuals from two unrelated Chinese families, and 100 healthy donors were recruited and genomic DNA was extracted. PPD was diagnosed based on the clinical manifestations, physical examination, characteristics of their bones on X-ray and laboratory results. All 5 exons and their exon-intron boundaries of the WISP3 gene were amplified by polymerase chain reaction (PCR) and sequenced directly.
  
  
  RESULTS
  In family 1, we identified that the proband (IV4) carried a novel non-sense mutation (G46X) which consisted of a homozygous C to T transition at c.8004 in exon 3. This mutation changed codon CAG to TAG and resulted in a subsequent change of the glutamine codon to stop codon and truncation at p. 46. In family 2, a novel missense mutation (C114Y) was found in the three patients (IV6, IV7, IV8), namely, a homozygous G to A transition at c.8209 in exon 3, which resulted in a cysteine (TGT) to tyrosine (TAT) substitution at p.114. Neither G46X nor C114Y was found in 100 normal controls. Meanwhile, we found that these patients had some different phenotypes, compared with the affected individuals with PPD from cases reported previously.
  
  
  CONCLUSIONS
  Our study suggests that the novel G46X and C114Y mutations in exon 3 in WISP3 gene are responsible for PPD in Chinese patients. Furthermore, many heterozygous carriers (c.8004C>T and c.8209G>A) are found in the two families, suggesting the existence of a founder effect in the locality where they live, respectively.
authors.affiliation: Department of Osteoporosis, Metabolic Bone Disease and Genetic Research Unit, Shanghai Jiao Tong University Affiliated the Sixth People's Hospital, Shanghai 200233, 600 Yi-Shan Rd., PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Yue
authors.forename: Zhen-Lin
authors.initials: ZL
authors.lastname: Zhang
authors.forename: Jin-Wei
authors.initials: JW
authors.lastname: He
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D044466:Asian People; D001483:Base Sequence; D055511:CCN Intercellular Signaling Proteins; D005190:Family; D005260:Female; D018703:Founder Effect; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology*; D010375:Pedigree; D016133:Polymerase Chain Reaction
chemical_list: D055511:CCN Intercellular Signaling Proteins; C400081:CCN6 protein, human; D018969:Insulin-Like Growth Factor Binding Proteins