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

  1. David J. Lloyd2,3,
  2. Matthew C. Wheeler1 and
  3. Nicholas Gekakis (gekakis{at}scripps.edu)1
  1. 1The Scripps Research Institute, 10550 North Torrey Pines Rd, La Jolla, CA 92037
  2. 2Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, La Jolla, CA 92121
  3. 3Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320

    Abstract

    Objective: Type 2 diabetes (T2D) 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 ENU-mutagenized C57BL/6 mice were bred to homozygosity, maintained on high fat diet (HFD), 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 histidine to tyrosine 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 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 phonotypically 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

      • Received October 3, 2008.
      • Accepted October 30, 2009.

    This Article

    1. Diabetes
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