Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein

Wolf ram syndrome is an autosomal recessive disorder characterized by juven ile diabetes mellitus, diabetes insipidus, optic atrophy and a number of ne urological symptoms including deafness, ataxia and peripheral neuropathy. M itochondrial DNA deletions have been described in a few patients and a locu s has been mapped to 4p16 by linkage analysis. Susceptibility to psychiatri c illness is reported to be high in affected individuals and increased in h eterozygous carriers in Wolf ram syndrome families. We screened four candid ate genes in a refined critical linkage interval covered by an unfinished g enomic sequence of 600 kb, One of these genes, subsequently named wolframin , codes for a predicted transmembrane protein which was expressed in variou s tissues, including brain and pancreas, and carried loss-of-function mutat ions in both alleles in Wolf ram syndrome patients.