Phenotype-genotype correlations in a series of Wolfram syndrome families

OBJECTIVE - Wolfram syndrome is an extremely rare autosomal-recessive disorder that predisposes the development of type 1 diabetes in association With progressive optic atrophy. The genetic basis of this disease has been shown to be due to mutations in the WFS1 gene. The WFS1 gene encodes a novel transmembrane protein called wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic beta-cells and neurons. Genotype-phenotype correlations in this syndrome are becoming apparent and may help in explaining some of the variable characteristics observed in this disease. RESEARCH DESIGN AND METHODS - in this report, we have Studied 13 patients -,with Wolfram syndrome from nine families to further define the relationship between mutation Site and type With specific disease characteristics. RESULTS - A severe phenotype was seen in patients with mutations in exon 4 and with a large deletion encompassing most of exert 8. In total, nine novel mutations were identified as well as three new silent polymorphisms. CONCLUSIONS - Similar to all Other Mutation reports, most causative changes identified in the WFS1 gene occurred in exon 8, and only one was identified Outside this region in exon 4.