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) syndrom e. It is suggested that the WFS1 protein is important in the survival of is let p-cells. We studied the WFS1 gene in a Japanese population to assess it s possible role in common type 1 diabetes. Mutation screening revealed four missense mutations; R456H, G576S, H611R, and 1720V. 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 compar ed to the control group (P = 0.0005); H611R and 1720V were also significant ly increased with weaker significance. Furthermore, in patients with the R4 56H mutation, type 1 diabetes-resistant HLA-DRB1 alleles (DRB1*0406, 1501, and 1502) were significantly increased compared to mutation-negative patien ts 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 g ene may have a role in the development of common type 1 diabetes as a nonau toimmune genetic basis. (C) 2000 Academic Press.