A point mutation in Sec61alpha1 leads to diabetes and hepatosteatosis in mice.
A point mutation in Sec61alpha1 leads to diabetes and hepatosteatosis in mice.
复制标题
Sec61alpha1中的一个点突变导致小鼠糖尿病和肝脏tososisosis。
作者：
Lloyd DJ;Wheeler MC;Gekakis N
2型糖尿病是由环境和遗传因素引起的。为了更好地了解遗传因素，我们使用正向遗传学来发现以前没有参与高血糖症或糖尿病发展的基因。将乙基亚硝基脲诱变的C57 BL/6小鼠的后代繁殖至纯合性，维持高脂饮食，并筛选高血糖症。一个糖尿病小鼠家族的表型在具有单核苷酸多态性标记的杂交F2中作图，随后进行候选基因测序以鉴定携带致病突变的基因。在纯C57 BL/6背景下对野生型、杂合和纯合突变小鼠进行后续分析。糖尿病定位于Sec 61 a1基因中的点突变，该基因编码氨基酸344处的His至Tyr取代（Y344 H）。代谢分析、组织学检查和电子显微镜检查显示，高血糖症是由于内质网（ER）应激引起的β细胞凋亡导致胰岛素不足的结果。Sec 61 a1在突变小鼠中的转基因β细胞特异性表达挽救了糖尿病、β细胞凋亡和ER应激体外实验表明Sec 61 α1在β细胞对葡萄糖的反应中起关键作用。在这里，我们表型特征糖尿病小鼠与一个新的点突变的基本组成部分细胞的ER蛋白易位机制，Sec 61 α1。突变蛋白的易位似乎不受影响。相反，ER稳态被扰乱，导致β细胞死亡和糖尿病。
Type 2 diabetes is caused by both environmental and genetic factors. To better understand the genetic factors we used forward genetics to discover genes that have not previously been implicated in the development of hyperglycemia or diabetes. Offspring of ethylnitrosurea-mutagenized C57BL/6 mice were bred to homozygosity, maintained on high-fat diet, and screened for hyperglycemia. The phenotype in one diabetic family of mice was mapped among hybrid F2s with single nucleotide polymorphic markers, followed by candidate gene sequencing to identify the gene harboring the causative mutation. Subsequent analysis was done on wild-type, heterozygous, and homozygous mutant mice on a pure C57BL/6 background. Diabetes mapped to a point mutation in the Sec61a1 gene that encodes a His to Tyr substitution at amino acid 344 (Y344H). Metabolic profiling, histological examination, and electron microscopy revealed that hyperglycemia was a result of insulin insufficiency due to β-cell apoptosis brought on by endoplasmic reticulum (ER) stress. Transgenic β-cell–specific expression of Sec61a1 in mutant mice rescued diabetes, β-cell apoptosis, and ER stress. In vitro experiments showed that Sec61α1 plays a critical role in the β-cell response to glucose. Here we phenotypically characterize diabetes in mice with a novel point mutation in a basic component of the cell's ER protein translocation machinery, Sec61α1. Translocation by the mutant protein does not appear to be affected. Rather, ER homeostasis is perturbed leading to β-cell death and diabetes.
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