WFS1/wolframin mutations, Wolfram syndrome, and associated diseases.
Wolfram syndrome (WS) is the inherited association of juvenile-onset insulin-dependant diabetes mellitus and progressive bilateral optic atrophy. A nuclear gene, WFS1/wolframin, was identified that segregated with disease status and demonstrated an autosomal recessive mode of inheritance. Mutation analysis of the WFS1 gene in WS patients has identified mutations in 90% of patients. Most were compound heterozygotes with private mutations distributed throughout the gene with no obvious hotspots. The private nature of the mutations in WS patients and the low frequencies make it difficult to determine the biological or clinical relevance of these mutations. Mutation screening in patients with psychiatric disorders or diabetes mellitus has also been performed to test the hypothesis that heterozygous carriers of WFS1 gene mutations are at an increased risk following the observation that WS first-degree relatives have a higher frequency of these disorders. Most studies showed no association, however two missense mutations were identified that demonstrated significant association with psychiatric disorders and diabetes mellitus. Population association studies and functional studies of these variants will need to be performed to confirm these preliminary results. The elucidation of functions and functional pathways for the WFS1 gene product 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 and associated disorders.