A Point Mutation in Sec61α1 Leads to Diabetes and Hepatosteatosis in Mice

  1. David J. Lloyd1,2,
  2. Matthew C. Wheeler3 and
  3. Nicholas Gekakis3
  1. 1Genomics Institute of the Novartis Research Foundation, San Diego, California;
  2. 2Amgen, Thousand Oaks, California;
  3. 3The Scripps Research Institute, La Jolla, California.
  1. Corresponding author: Nicholas Gekakis, gekakis{at}scripps.edu.
  1. D.J.L. and M.C.W. contributed equally to this work.

Abstract

OBJECTIVE 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.

RESEARCH DESIGN AND METHODS 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.

RESULTS 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.

CONCLUSIONS 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.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received October 3, 2008.
    • Accepted October 30, 2009.
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  1. Diabetes vol. 59 no. 2 460-470
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