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Molecular investigations to improve diagnostic accuracy in patients with ARC syndrome
Author(s) -
Cullinane Andrew R.,
StraatmanIwanowska Anna,
Seo Jeong K.,
Ko Jae S.,
Song Kyung S.,
Gizewska Maria,
Gruszfeld Dariusz,
Gliwicz Dorota,
Tuysuz Beyhan,
Erdemir Gulin,
Sougrat Rachid,
Wakabayashi Yoshiyuki,
Hinds Rupert,
Barnicoat Angela,
Mandel Hanna,
Chitayat David,
Fischler Björn,
GarciaCazorla Angels,
Knisely A. S.,
Kelly Deirdre A.,
Maher Eamonn R.,
Gissen Paul
Publication year - 2009
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20900
Subject(s) - arc (geometry) , biology , mutation , germline , phenotype , germline mutation , genetics , gene , pathology , medicine , geometry , mathematics
Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome is a multi‐system autosomal recessive disorder caused by germline mutations in VPS33B. The detection of germline VPS33B mutations removes the need for diagnostic organ biopsies (these carry a>50% risk of life‐threatening haemorrhage due to platelet dysfunction); however, VPS33B mutations are not detectable in∼25% of patients. In order further to define the molecular basis of ARC we performed mutation analysis and mRNA and protein studies in patients with a clinical diagnosis of ARC. Here we report novel mutations in VPS33B in patients from Eastern Europe and South East Asia. One of the mutations was present in 7 unrelated Korean patients. Reduced expression of VPS33B and cellular phenotype was detected in fibroblasts from patients clinically diagnosed with ARC with and without known VPS33B mutations. One mutation‐negative patient was found to have normal mRNA and protein levels. This patient's clinical condition improved and he is alive at the age of 2.5 years. Thus we show that all patients with a classical clinical course of ARC had decreased expression of VPS33B whereas normal VPS33B expression was associated with good prognosis despite initial diagnosis of ARC. © 2008 Wiley‐Liss, Inc.