Clinical and Molecular Genetic Analysis of 19 Wolfram Syndrome Kindreds Demonstrating a Wide Spectrum of Mutations in WFS1

Abstract

Wolfram syndrome is an autosomal recessive neurodegenerative disorder characterized by juvenile-onset diabetes mellitus and progressive optic atrophy. mtDNA deletions have been described, and a gene (WFS1) recently has been identified, on chromosome 4p16, encoding a predicted 890 amino acid transmembrane protein. Direct DNA sequencing was done to screen the entire coding region of the WFS1 gene in 30 patients from 19 British kindreds with Wolfram syndrome. DNA was also screened for structural rearrangements (deletions and duplications) and point mutations in mtDNA. No pathogenic mtDNA mutations were found in our cohort. We identified 24 mutations in the WFS1 gene: 8 nonsense mutations, 8 missense mutations, 3 in-frame deletions, 1 in-frame insertion, and 4 frameshift mutations. Of these, 23 were novel mutations, and most occurred in exon 8. The majority of patients were compound heterozygotes for two mutations, and there was no common founder mutation. The data were also analyzed for genotype-phenotype relationships. Although some interesting cases were noted, consideration of the small sample size and frequency of each mutation indicated no clear-cut correlations between any of the observed mutations and disease severity. There were no obvious mutation hot spots or clusters. Hence, molecular screening for Wolfram syndrome in affected families and for Wolfram syndrome-carrier status in subjects with psychiatric disorders or diabetes mellitus will require complete analysis of exon 8 and upstream exons.

Identification of homozygous WFS1 mutations (p.Asp211Asn, p.Gln486*) causing severe Wolfram syndrome and first report of male fertility

“…To date, seven causative mutations have been identified within exon 5, of which five mutations [17][18][19]25,26 result in WFS, whereas two mutations 27,28 are associated with low-frequency sensorineural hearing loss. p.Asp211Asn is located in the N-terminal domain of the WFS1 protein.…”

“…8,9 Although many mutations have been identified in the WFS1 gene, most affected patients carry a mutation, either insertion, deletion, nonsense or missense, in exon 8, the largest exon of WFS1. 8,9,[16][17][18][19] The C-terminal hydrophilic part of the protein is the major site for missense mutations. Studies indicate that mutations affecting the translation of the last 10-15 amino acids result in a severe disease phenotype that confirms the functional importance of the C-terminus.…”

“…Studies indicate that mutations affecting the translation of the last 10-15 amino acids result in a severe disease phenotype that confirms the functional importance of the C-terminus. 17,20 The exact function of WFS1 Wolframin protein is still unknown. There is also no clear genotype-phenotype correlation.…”

Genetics of type 1 diabetes mellitus

“…215 The region incorporates the Wolfram syndrome (phenotype includes insulin-dependent diabetes and optic atrophy) locus, WFS1. 216,217 Several mutations have been identified in WFS1, [216][217][218] and it has been suggested that variations in the WFS1 locus could play a minor role in the more common forms of diabetes mellitus. 216 Thus, these examples suggest that genes identified in oligogenic forms of diabetes may contribute to T1D susceptibility in the general population.…”

Molecular detection of novel WFS1 mutations in patients with Wolfram syndrome by a DHPLC-based assay

“…The observed consanguinity in about 25% of patients of different ethnicity [Gerbitz, 1999;Gomez-Zaera et al, 2001] is further evidence of a mendelian recessive mode of inheritance of the disorder. Actually, most WS patients carry loss-of-function mutations in the WFS1 gene (MIM# 606201), located at chromosome 4p16.1 and spanning a genomic region of 33.44 Kb [Hardy et al, 1999;Inoue et al, 1998]. Nevertheless, the recent identification of a second locus involved in WS (WFS2; MIM# 604928), mapped on chromosome 4q22-q24 [El-Shanti et al, 2000] has definitely confirmed the locus heterogeneity of this syndrome, hypothesized in the past [Collier et al, 1996].…”