Molecular investigations to improve diagnostic accuracy in patients with ARC syndrome.

Hum Mutat 2009 Feb;30(2):E330-7

Department of Medical and Molecular Genetics, University of Birmingham, Birmingham, UK.

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 approximately 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.

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.20900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635429PMC
February 2009
52 Reads

Publication Analysis

Top Keywords

vps33b mutations
12
mrna protein
8
mutations vps33b
8
vps33b
8
arc syndrome
8
expression vps33b
8
diagnosis arc
8
arc
7
patients
7
mutations
6
define molecular
4
clinically diagnosed
4
arc performed
4
arc vps33b
4
diagnosed arc
4
molecular basis
4
basis arc
4
patients order
4
dysfunction vps33b
4
normal mrna
4

Similar Publications