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
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
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DOI：
10.1006/bbrc.2000.2169
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发表时间：
2000-02-16
影响因子：
3.1
通讯作者：
Katayama, S
中科院分区：
文献类型：
--
作者：
Awata, T;Inoue, K;Katayama, S
最近，一个新的基因为一个假定的跨膜蛋白（WFS 1/wolframin）被发现在Wolfram综合征或DI-DM-OA-D（尿崩症，糖尿病，视神经萎缩，耳聋）综合征患者突变。提示WFS 1蛋白在胰岛β细胞的存活中起重要作用。我们研究了日本人群中的WFS 1基因，以评估其在常见1型糖尿病中的可能作用。突变筛查发现了四个错义突变：R456 H、G576 S、H611 R和1720 V。通过对185例1型糖尿病患者和380例对照者的遗传关联研究，发现1型糖尿病组R456 H较对照组显著增高（P = 0.0005），H611 R和1720 V也显著增高，但意义较弱。此外，在R456 H突变患者中，1型糖尿病耐药HLA-DRB 1等位基因（DRB 1 *0406、1501和1502）与突变阴性患者相比显著增加，而易感DRB 1 *0901显著减少。与R456 H阴性患者相比，R456 H阳性患者的自身免疫特征（伊卡或GAD-Ab阳性和自身免疫性甲状腺疾病的组合）频率降低。这些数据表明，WFS 1基因可能在1型糖尿病的发展中发挥作用，作为非自身免疫性遗传基础。(C)北京大学出版社.
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 p-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 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 compared to the control group (P = 0.0005); H611R and 1720V 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. (C) 2000 Academic Press.