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.
Awata
T
T
The Fourth Department of Medicine, Saitama Medical School, Saitama, Japan. awata@saitama-med.ac.jp
Inoue
K
K
Kurihara
S
S
Ohkubo
T
T
Inoue
I
I
Abe
T
T
Takino
H
H
Kanazawa
Y
Y
Katayama
S
S
D000328:Adult; D000368:Aged; D000483:Alleles; D001120:Arginine / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006639:Histidine / Q000235:genetics; D006801:Humans; D007564:Japan; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D014929:Wolfram Syndrome / Q000235:genetics*
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D008565:Membrane Proteins; C114987:wolframin protein; D006639:Histidine; D001120:Arginine