Novel and Recurrent Mutations of WISP3 in Two Chinese Families with Progressive Pseudorheumatoid Dysplasia

Jing Sun,Yan Jiang,Xueying Zhou,Weibo Xia,Xiaoping Xing,Shuli He,Xunwu Meng,Ou Wang,Mei Li,Min Nie,Zhen Zhao,Gisela Nogales-Gadea

doi:10.1371/journal.pone.0038643

Abstract

BackgroundThe WNT1-inducible signaling pathway protein 3 (WISP3), which belongs to the CCN (cysteine-rich protein 61, connective tissue growth factor, nephroblastoma overexpressed) family, is a secreted cysteine-rich matricellular protein that is involved in chondrogenesis, osteogenesis and tumorigenesis. WISP3 gene mutations are associated with progressive pseudorheumatoid dysplasia (PPD, OMIM208230), an autosomal recessive genetic disease that is characterized by the swelling of multiple joints and disproportionate dwarfism.Methodology/Principal FindingsFour PPD patients from two unrelated Chinese families were recruited for this study. The clinical diagnosis was confirmed by medical history, physical examinations, laboratory results and radiological abnormalities. WISP3 mutations were detected by direct DNA sequence analysis. In total, four different mutations were identified, which consisted of two missense mutations, one deletion and one insertion that spanned exons 3, 5 and 6 of the WISP3 gene. One of the missense mutations (c.342T>G/p.C114W) and a seven-base pair frameshift deletion (c.716_722del/p.E239fs*16) were novel. The other missense mutation (c.1000T>C/p. S334P) and the insertion mutation (c.866_867insA/p.Q289fs*31) had previously been identified in Chinese patients. All four cases had a compound heterozygous status, and their parents were heterozygous carriers of these mutations.Conclusions/SignificanceThe results of our study expand the spectrum of WISP3 mutations that are associated with PPD and further elucidate the function of WISP3.

Highlights

Progressive pseudorheumatoid dysplasia (PPD, OMIM208230), referred to as spondyloepiphyseal dysplasia tarda with progressive arthropathy (SEDT-PA) or progressive pseudorheumatoid arthritis of childhood (PPAC), is an autosomal recessive genetic disease
1 consists of 2 brothers who were affected with PPD with different degrees of severity
The proband (II 2 in family 1), a 5-year-old boy, was referred to our clinic in October 2005. His parents communicated the boy’s complaint of multiple joint swelling, which began at the age of 4

Summary

Introduction

Progressive pseudorheumatoid dysplasia (PPD, OMIM208230), referred to as spondyloepiphyseal dysplasia tarda with progressive arthropathy (SEDT-PA) or progressive pseudorheumatoid arthritis of childhood (PPAC), is an autosomal recessive genetic disease. The disorder manifests prominently in the skeletal system and presents with a disproportionately short stature, i.e., a short neck and trunk, and progressive swelling and stiffness in multiple joints. The PPD population incidence, which is extremely low, is estimated to be one person per million in the UK [1]. Most PPD cases may remain undiagnosed because of the similar skeletal abnormalities shared with other arthropathies, spondyloepiphyseal dysplasia and glycogen storage diseases. WISP3 gene mutations are associated with progressive pseudorheumatoid dysplasia (PPD, OMIM208230), an autosomal recessive genetic disease that is characterized by the swelling of multiple joints and disproportionate dwarfism

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Conclusion