A point mutation in Sec61alpha1 leads to diabetes and hepatosteatosis in mice.

Diabetes
David J LloydNicholas Gekakis

Abstract

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 beta-cell apoptosis brought on by endoplasmic reticulum (ER) stress. Transgenic beta-cell-specific expression of Sec61a1 in mutant mice rescued diabetes, beta-cell apoptosis, and ER stress. In vitro experiments showed that Sec61alpha1 plays a critical role in the beta-cel...Continue Reading

References

Jul 1, 1978·The Journal of Cell Biology·N B GilulaW H Beers
Jul 9, 2002·Apoptosis : an International Journal on Programmed Cell Death·Seiichi OyadomariM Mori
Dec 12, 2002·Diabetes·Heather P Harding, David Ron
Dec 28, 2002·Diabetes·Alexandra E ButlerPeter C Butler
Feb 14, 2003·Internal Medicine·Eiichi ArakiMasataka Mori
Mar 4, 2003·Proceedings of the National Academy of Sciences of the United States of America·Tim WiltshireColin F Fletcher
Apr 6, 2004·Proceedings of the National Academy of Sciences of the United States of America·Ben G WenMichael P Cooke
Oct 16, 2004·Science·Umut OzcanGökhan S Hotamisligil
Jun 3, 2005·The Journal of Clinical Investigation·M Alan PermuttNancy Cox
Jun 15, 2005·Annual Review of Biochemistry·Martin Schröder, Randal J Kaufman
Apr 29, 2006·Human Molecular Genetics·David J LloydNicholas Gekakis
Dec 15, 2006·Nature·Steven E KahnKristina M Utzschneider
Apr 28, 2007·Science·UNKNOWN Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical RShaun Purcell
Jul 3, 2007·Nature Genetics·Manjinder S SandhuInês Barroso
Sep 15, 2007·Proceedings of the National Academy of Sciences of the United States of America·Julie StøyUNKNOWN Neonatal Diabetes International Collaborative Group
Dec 12, 2007·Biochemical and Biophysical Research Communications·Kazutomi YoshiuchiMunehide Matsuhisa

❮ Previous
Next ❯

Citations

Oct 2, 2013·Human Reproduction Update·Catherine E Aiken, Susan E Ozanne
Oct 19, 2011·The Journal of Infectious Diseases·Ayaka IwasaYoshihiro Kawaoka
Dec 4, 2010·Toxicological Sciences : an Official Journal of the Society of Toxicology·Donald G RobertsonMichael D Reily
Oct 16, 2010·American Journal of Physiology. Gastrointestinal and Liver Physiology·Nhung NguyenIan R van Driel
Dec 10, 2013·BMC Cell Biology·Thomas TretterKarin Römisch
Apr 8, 2014·Antioxidants & Redox Signaling·Stewart Siyan Cao, Randal J Kaufman
Jun 18, 2014·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Sarah HaßdenteufelRichard Zimmermann
Mar 27, 2013·Seminars in Immunopathology·Takao Iwawaki, Daisuke Oikawa
Jun 27, 2014·Journal of Molecular Biology·Johanna DudekRichard Zimmermann
Jul 17, 2012·The EMBO Journal·Nico SchäubleRichard Zimmermann
Oct 10, 2012·Biochemical and Biophysical Research Communications·Matthew C Wheeler, Nicholas Gekakis
Jan 18, 2013·Expert Opinion on Therapeutic Targets·Stewart Siyan Cao, Randal J Kaufman
Dec 15, 2010·Journal of Hepatology·Harmeet Malhi, Randal J Kaufman
Jul 6, 2010·Biochimica Et Biophysica Acta·Richard ZimmermannVolkhard Helms
Feb 7, 2015·PloS One·Marie-Luise Kaiser, Karin Römisch
Jun 15, 2014·Journal of Lipid Research·Matthew C Wheeler, Nicholas Gekakis
Feb 13, 2019·Journal of the American Society of Nephrology : JASN·Yasunobu IshikawaStefan Somlo
Jul 22, 2019·FEBS Letters·Sarah HaßdenteufelRichard Zimmermann
Dec 5, 2019·Endocrinology·Irina X ZhangLeslie S Satin
Nov 23, 2017·Frontiers in Physiology·Sven LangRichard Zimmermann
Dec 22, 2017·Signal Transduction and Targeted Therapy·Maximilian LinxweilerRichard Zimmermann
Apr 8, 2020·Laboratory animal research·Daejin HyungJe Kyung Seong
Aug 8, 2017·The Journal of Allergy and Clinical Immunology·Desirée SchubertBodo Grimbacher

❮ Previous
Next ❯

Methods Mentioned

BETA
enzyme-linked immunosorbent assay
genotyping
PCR
electron microscopy
immunoprecipitation
Assay
transgenic
RIP-Sec
transfection

Software Mentioned

ImageJ

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

American Diabetes Association Journals

Discover the latest diabetes research published by the journals from the American Diabetes Association.