Abstract
OBJECTIVEType 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.RESEARCH DESIGN AND METHODSOffspring 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.RESULTSDiabetes 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.CONCLUSIONSHere 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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