C57BL/6J-Sec61a1^m1Gek/J

Stock number: 016131
Research areas: Cardiovascular Research, Cell Biology Research, Diabetes and Obesity Research, Endocrine Deficiency Research, Internal/Organ Research, Metabolism Research, Neurobiology Research, Research Tools

Description

The Sec61a1^Y344H mutation is an ENU-induced missense histidine to tyrosine substitution at amino acid 344 of the Sec61 alpha 1 subunit (S. cerevisiae) gene that renders mice diabetic. These Sec61a1^Y344H mutant mice may be useful in studying diabetes, ER protein trafficking/processing/secretion, ER stress, obesity, fat metabolism, and other high-fat diet-associated disorders.

Detailed description

Mice homozygous for the ENU-induced missense mutation, called Sec61a1^Y344H, are viable and fertile. By ~4 weeks of age, homozygous males and females maintained on a high-fat diet (~58% kcal from fat) become diabetic (hyperglycemic) with hypoinsulinemia; the result of endoplasmic reticulum (ER) stress-induced apoptosis of pancreatic β-cells. In addition to diabetes, these mice exhibit other metabolic, endocrinological, and growth abnormalities (including hyperlipidemia, hepatosteatosis, hypercholesterolemia, hypertriglyceridemia, and, in older mice, hepatic cirrhosis). Homozygous mice maintained on a chow diet (~5% kcal from fat) become diabetic by ~10 weeks of age; exhibiting hyperglycemia, hypoinsulinemia, glucose intolerance, and pancreatic β-cell loss. Heterozygous mice have an intermediate hypoinsulinemic phenotype on high-fat diet. These Sec61a1^Y344H mutant mice may be useful in studying diabetes, ER protein trafficking/processing/secretion, ER stress, obesity, fat metabolism, and other high-fat diet-associated disorders.

Development

Following multidose N-ethyl-N-nitrosourea (ENU) treatments to induce mutations in founder C57BL/6J mice, a forward genetic screen was utilized to identify a family of mice that exhibited hyperglycemia (diabetes) when maintained on a high-fat diet (~58% kcal from fat). The diabetic phenotype was mapped to a region of chromosome 6 containing the Sec61 alpha 1 subunit (S. cerevisiae) gene (Sec61a1). Sequencing of this gene identified a T->C transition within exon 10 that encodes a histidine to tyrosine substitution at amino acid 344 (part of a double Tyr motif highly conserved from bacteria to mammals). Mice harboring this ENU-induced missense mutation, called Sec61a1^Y344H (or Sec61a1^m1Gek), were maintained on a C57BL/6J genetic background (with at least five backcrosses to C57BL/6J) prior to arrival at The Jackson Laboratory Repository. Upon arrival, mutant mice were bred with C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony. Of note, the donating investigator reports that because these mice have been backcrossed many generations to C57BL/6J mice, the number of other ENU-induced mutations should be greatly reduced, but not eliminated altogether.

Allele

Symbol: Sec61a1^m1Gek
Name: mutation 1, Nicholas Gekakis
MGI accession ID: MGI:4830998
Generation method: Chemically induced (ENU)
Marker symbol: Sec61a1
Marker name: Sec61 alpha 1 subunit (S. cerevisiae)
Chromosome: 6
Strain of origin: C57BL/6J
Molecular note: ENU mutagenesis induced a T to C transition at codon 344 that results in an amino substitution of histidine for tyrosine at position 344 (Y344H).