Missense variations of the gene responsible for Wolfram syndrome (WFS1/wolframin) in Japanese: possible contribution of the Arg456His mutation to type 1 diabetes as a nonautoimmune genetic basis.

Recently, a novel gene for a putative transmembrane protein (WFS1/wolframin) was found to be mutated in patients with Wolfram syndrome or DI-DM-OA-D (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome. It is suggested that the WFS1 protein is important in the survival of islet beta-cells. We studied the WFS1 gene in a Japanese population to assess its possible role in common type 1 diabetes. Mutation screening revealed four missense mutations; R456H, G576S, H611R, and I720V. By genetic association studies of 185 type 1 diabetes patients and 380 control subjects, we found that R456H was significantly increased in the type 1 diabetes group compared to the control group (P = 0.0005); H611R and I720V were also significantly increased with weaker significance. Furthermore, in patients with the R456H mutation, type 1 diabetes-resistant HLA-DRB1 alleles (DRB1*0406, 1501, and 1502) were significantly increased compared to mutation-negative patients while susceptible DRB1*0901 was significantly decreased. Frequencies of autoimmunity characteristics (ICA or GAD-Ab positiveness and combination of autoimmune thyroid disease) were decreased in the R456H-positive patients compared to the R456H-negative patients. These data suggest that the WFS1 gene may have a role in the development of common type 1 diabetes as a nonautoimmune genetic basis. Copyright 2000 Academic Press.