These double mutant mice carry the Akita mutation, characterized by early-onset NIDDM, and an Ldlr knock-out, characterized by increased plasma cholesterol levels.
Dr. Jan L. Breslow, Rockefeller University
Genetic Background | Generation |
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|
Allele Type | Gene Symbol | Gene Name |
---|---|---|
Targeted (Null/Knockout) | Ldlr | low density lipoprotein receptor |
Allele Type | Gene Symbol | Gene Name |
---|---|---|
Spontaneous | Ins2 | insulin II |
Mice homozygous for the Akita spontaneous mutation die postnatally, typically by 12 weeks of age. Independently, heterozygous Akita mutant mice are a model of insulin dependent diabetes mellitus (IDDM) with severe hyperglycemia (see the datasheet for Stock No. 003548 for additional information). LDLR-null homozygotes have elevated serum cholesterol levels (200-400 mg/dl) which can escalate to very high levels (> 2000 mg/dl) when the mice are fed a high fat diet. LDLR-deficient mice also are predisposed to develop atherosclerosis. These double mutant mice may be useful in studies of diabetes, metabolism, hyperglycemia, atherosclerosis, hypercholesterolemia, and diabetes-related macrovascular complications.
The Ldlrtm1Her mutation was made by Dr. Robert Hammer and Joachim Herz (HHMI, University of Texas Southwestern Medical Center). Briefly, a targeting vector was used to insert a neo cassette into exon 4. The vector was electroporated into 129S7/SvEvBrd-derived AB1 embryonic stem (ES) cells. Chimeric mice were bred to C57BL/6J, and the strain was made congenic on a C57BL/6J genetic background at The Jackson Laboratory (Stock No. 002207). The Akita spontaneous mutation in the insulin II gene (originally called Mody4) was identified on the C57BL/6NScl genetic background by Dr. Akio Koizumi (The Akita University School of Medicine). These mice were shipped to The Jackson Laboratory and then backcrossed on to the C57BL/6J genetic background (Stock No. 003548). To generate the double mutant strain, Stock No. 002207 mice were bred with Stock No. 003548 mice in the laboratory of Dr. Jan Breslow at The Rockefeller University. Double mutant mice were then backcrossed to C57BL/6J for approximately 7 generations prior to arrival at The Jackson Laboratory. The donating investigators indicate that 103/104 microsatellite markers indicate C57BL/6J background. The single exception is D7Mit81.
Allele Name | targeted mutation 1, Joachim Herz |
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Allele Type | Targeted (Null/Knockout) |
Allele Synonym(s) | LDLR-; LDLR KO; LDLr0; LDLrKO; LDLr-KO; Ldlrtm1Her |
Gene Symbol and Name | Ldlr, low density lipoprotein receptor |
Gene Synonym(s) | |
Site of Expression | Immunoblot analysis of liver membranes detected a truncated protein in homozygous mutant animals. |
Strain of Origin | 129S7/SvEvBrd-Hprt+ |
Chromosome | 9 |
General Note | When used in bone marrow transplant into Ldlrtm1Her homozygous mice, Abca1tm1Jdm Abcg1tm1Dgen homozygous cells accelerate the development of atherosclerosis. (J:130777) Phenotypic Similarity to Human Syndrome: Atherosclerosis, Susceptibility to J:29950, J:225091 in mice fed a high-cholesterol diet. |
Molecular Note | Insertion of a neomycin resistance cassette into exon 4. The authors predict that the targeted allele would encode a truncated non-functional protein that will not bind LDL, and that lacks a membrane spanning segment. Immunoblot analysis of liver membranes detected a truncated protein in homozygous mutant animals. |
Mutations Made By | Dr. Joachim Herz, Univ of Texas Southwest Med Ctr Dallas |
Allele Name | Akita |
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Allele Type | Spontaneous |
Allele Synonym(s) | Akita; AkitaIns2; Ins2C96Y; Ins2Mody; Mody; Mody4 |
Gene Symbol and Name | Ins2, insulin II |
Gene Synonym(s) | |
Strain of Origin | C57BL/6NSlc |
Chromosome | 7 |
Molecular Note | In the mutant allele a transition from G-to-A at coding nucleotide 287 disrupts an Fnu4HI site in exon 3. This mutation changed the seventh amino acid in the A chain of mature insulin, Cys96 (TGC), to Tyr (TAC) (p.C96Y). The authors predict that the transition would disrupt a disulfide bond between the A and the B chains and would likely induce a major conformational change in insulin 2 molecules. RT-PCR studies suggest that both normal and mutant Ins2 alleles are transcribed similarly in pancreatic islets of heterozygous mice, although immunofluorescence and immunoblot analyses of heterozygous islets detected reduced levels of insulin and proinsulin. |
When maintaining a live colony, these mice are bred as heterozygous for the Akita mutation and homozygous for the LDLR mutation.
When using the Akita LDLR KO mouse strain in a publication, please cite the originating article(s) and include JAX stock #006580 in your Materials and Methods section.
Facility Barrier Level Descriptions
Service/Product | Description | Price |
---|---|---|
Heterozygous or Homozygous for Ldlr<tm1Her>, Heterozygous or Wild type for Ins2<Akita> |
Frozen Mouse Embryo | B6.Cg-Ins2<Akita> Ldlr<tm1Her>/J Frozen Embryos | $2595.00 |
Frozen Mouse Embryo | B6.Cg-Ins2<Akita> Ldlr<tm1Her>/J Frozen Embryos | $2595.00 |
Frozen Mouse Embryo | B6.Cg-Ins2<Akita> Ldlr<tm1Her>/J Frozen Embryos | $3373.50 |
Frozen Mouse Embryo | B6.Cg-Ins2<Akita> Ldlr<tm1Her>/J Frozen Embryos | $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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