WFS1/Wolframin mutations, Wolfram syndrome, and associated diseases

Wolfram syndrome (WS) is the inherited association of juvenile-onset insuli n dependant diabetes mellitus and progressive bilateral optic atrophy. A nu clear gene, WFS1/wolframin, was identified that segregated with disease sta tus and demonstrated an autosomal recessive mode of inheritance. Mutation a nalysis of the WFS1 gene in WS patients has identified mutations in 90% of patients. Most were compound heterozygotes with private mutations distribut ed throughout the gene with no obvious hotspots. The private nature of the mutations in WS patients and the low frequencies make it difficult to deter mine the biological or clinical relevance of these mutations. Mutation scre ening in patients with psychiatric disorders or diabetes mellitus has also been performed to test the hypothesis that heterozygous carriers of WFS1 ge ne mutations are at an increased risk following the observation that WS fir st degree relatives have a higher frequency of these disorders. Most studie s showed no association, however two missense mutations were identified tha t demonstrated significant association with psychiatric disorders and diabe tes mellitus. Population association studies and functional studies of thes e variants will need to be performed to confirm these preliminary results. The elucidation of functions and functional pathways for the WFS1 gene prod uct and variants will shed light on the effect of such disparate mutations on gene function and their role in the resulting clinical phenotype in WS a nd associated disorders. Hum Mutat 17:357-367, 2001. (C) 2001 Wiley-Liss, I nc.