Overview

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.

Donating Investigator

Nicholas Gekakis, San Diego State University

Genetic overview

Genetic Background	Generation

Sec61a1^m1Gek

Allele Type	Gene Symbol	Gene Name
Chemically induced (ENU)	Sec61a1	Sec61 alpha 1 subunit (S. cerevisiae)

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Research Applications

Diabetes and Obesity Research
Research Tools
Cardiovascular Research
Metabolism Research
Endocrine Deficiency Research
Internal/Organ Research
Neurobiology Research
Cell Biology Research

View All Research Applications

Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

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.

Control Suggestions

Wild-type from the colony
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Lloyd DJ; Wheeler MC; Gekakis N. 2010. A point mutation in Sec61alpha1 leads to diabetes and hepatosteatosis in mice. Diabetes 59(2):460-70PubMed: 19934005 MGI: J:164159

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Genetics

Sec61a1^m1Gek

Allele Symbol: Sec61a1^m1Gek

Allele Name	mutation 1, Nicholas Gekakis
Allele Type	Chemically induced (ENU)
Allele Synonym(s)	Sec61a1^Y344H
Gene Symbol and Name	Sec61a1, Sec61 alpha 1 subunit (S. cerevisiae)
Gene Synonym(s)
Strain of Origin	C57BL/6J
Chromosome	6
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).
Mutations Made By	Nicholas Gekakis, San Diego State University

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Diabetes and Obesity Research
- Hyperglycemia
  - diet-induced
  - more severe
- Insulin Receptors and Growth Factors
- Hypoinsulinemia
Research Tools
- Cardiovascular Research
- Diabetes and Obesity Research
- Endocrine Deficiency Research
- Metabolism Research
Cardiovascular Research
- Other
  - altered fat metabolism
  - altered lipoprotein profile
- Hypertriglyceridemia
- Hypercholesterolemia
Metabolism Research
- Lipid Metabolism
Endocrine Deficiency Research
- Adipose Defects
Internal/Organ Research
- Adipose Defects
Neurobiology Research
- Metabolic Defects
Cell Biology Research
- Protein Processing
- Vesicular Trafficking

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

Genotype: Sec61a1^m1Gek/Sec61a1⁺
C57BL/6J-Sec61a1

homeostasis/metabolism phenotype

decreased circulating insulin level
- when fed a high fat diet although not as severe as in homozygotes

hyperglycemia
- when fed a high fat diet although not as severe as in homozygotes

Genotype: Sec61a1^m1Gek/Sec61a1^m1Gek
C57BL/6J-Sec61a1

adipose tissue phenotype

decreased total body fat amount
- in female mice fed a high fat diet
- in male mice fed chow or a high fat diet

growth/size/body region phenotype

decreased body size
- in female mice fed a high fat diet
- in male mice fed chow or a high fat diet

decreased lean body mass
- in female mice fed a high fat diet
- in male mice fed chow or a high fat diet

enlarged liver
- in mice fed a high fat diet

homeostasis/metabolism phenotype

abnormal glucose homeostasis

decreased circulating insulin level
- in female mice fed a high fat diet
- in male mice fed chow or a high fat diet

hyperglycemia
- in female mice fed a high fat diet
- in male mice fed chow or a high fat diet

impaired glucose tolerance
- in mice fed chow or a high fat diet

increased circulating cholesterol level
- in mice fed a high fat diet

increased circulating glucagon level
- mice fed a high fat diet exhibit a trend towards increased plasma glucagon compared with similarly treated wild-type mice that does not reach statistical significance

increased circulating triglyceride level
- in mice fed a high fat diet

liver/biliary system phenotype

enlarged liver
- in mice fed a high fat diet

hepatic steatosis
- in mice fed a high fat diet

increased hepatocyte apoptosis
- at 8 and 12 weeks

increased hepatocyte proliferation
- at 8 and 12 weeks

liver cirrhosis
- in older mice when fed a high fat diet

pale liver
- in mice fed a high fat diet

cellular phenotype

increased hepatocyte apoptosis
- at 8 and 12 weeks

increased hepatocyte proliferation
- at 8 and 12 weeks

increased pancreatic beta cell apoptosis
- in mice fed a high fat diet

muscle phenotype

decreased skeletal muscle mass
- in mice fed a high fat diet

endocrine/exocrine gland phenotype

abnormal pancreatic beta cell morphology
- in mice fed chow or a high fat diet, beta cells exhibit distended endoplasmic reticulum unlike wild-type cells

abnormal pancreatic beta cell physiology
- in mice fed a high fat diet, beta cells exhibit increased expression of endoplasmic reticulum stress markers compared to in wild-type cells

abnormal pancreatic delta cell morphology
- delta cells in mice fed a high fat diet are mislocalized to the interior of the islet as opposed to the peripheral position as in wild-type mice

decreased pancreatic beta cell number
- 3 months after mice are fed chow or a high fat diet

increased pancreatic alpha cell number
- in mice fed a high fat diet

increased pancreatic beta cell apoptosis
- in mice fed a high fat diet

increased pancreatic delta cell number
- 3 months after high fat diet feeding

References

Lloyd DJ; Wheeler MC; Gekakis N. 2010. A point mutation in Sec61alpha1 leads to diabetes and hepatosteatosis in mice. Diabetes 59(2):460-70PubMed: 19934005 MGI: J:164159

Additional - Sec61a1^m1Gek related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Pyrosequencing:Sec61a1 PYRO
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, heterozygous mice may be bred together, to wildtype mice from the colony, or to C57BL/6J inbred mice (Stock No. 000664). While homozygous mice are viable and fertile, the donating investigator reports that homozygous matings generate smaller litter sizes with more frequent pup lethality. Additionally, older homozygous females may exhibit more infertility.
- Additional Breeding and Husbandry Support
Citation
When using the C57BL/6J-Sec61a1^m1Gek/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #016131 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or wildtype for Sec61a1<m1Gek>

Related Products and Services

Frozen Mouse Embryo	C57BL/6J-Sec61a1<m1Gek>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	C57BL/6J-Sec61a1<m1Gek>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	C57BL/6J-Sec61a1<m1Gek>/J Frozen Embryo	$3373.50
Frozen Mouse Embryo	C57BL/6J-Sec61a1<m1Gek>/J Frozen Embryo	$3373.50

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Sec61a1m1Gek

Allele Symbol: Sec61a1m1Gek

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Mammalian Phenotype Terms by Genotype

Genotype: Sec61a1m1Gek/Sec61a1+C57BL/6J-Sec61a1

homeostasis/metabolism phenotype

Genotype: Sec61a1m1Gek/Sec61a1m1GekC57BL/6J-Sec61a1

adipose tissue phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

liver/biliary system phenotype

cellular phenotype

muscle phenotype

endocrine/exocrine gland phenotype

References

Additional - Sec61a1m1Gek related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Sec61a1^m1Gek

Allele Symbol: Sec61a1^m1Gek

Genotype: Sec61a1^m1Gek/Sec61a1⁺
C57BL/6J-Sec61a1

Genotype: Sec61a1^m1Gek/Sec61a1^m1Gek
C57BL/6J-Sec61a1

Additional - Sec61a1^m1Gek related