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
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 Synonym(s)||Akita; AkitaIns2; Ins2C96Y; Ins2Mody; Mody; Mody4|
|Gene Symbol and Name||Ins2, insulin II|
|Gene Synonym(s)||AA986540; CP-II; IDDM; IDDM1; IDDM2; ILPR; IRDN; Ins-2; Ins-2; InsII; MODY10; Mody; Mody; Mody4; Mody4; expressed sequence AA986540; maturity onset diabetes of the young; maturity onset diabetes of the young 4|
|Strain of Origin||C57BL/6NSlc|
|General Note||Phenotypic Similarity to Human Syndrome: Type 1 Diabetic Macrovascular Disease (J:174983)|
|Molecular Note||In the mutant allele a transition from G to A at nucleotide 1907 disrupted 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). 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.|
|Allele Name||targeted mutation 1, Joachim Herz|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||LDLR KO; LDLR-; LDLr-KO; LDLr0; LDLrKO; Ldlrtm1Her|
|Gene Symbol and Name||Ldlr, low density lipoprotein receptor|
|Gene Synonym(s)||FH; FHC; LDLCQ2; LDLRA|
|Site of Expression||Immunoblot analysis of liver membranes detected a truncated protein in homozygous mutant animals.|
|Strain of Origin||129S7/SvEvBrd-Hprt<+>|
|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: Type 1 Diabetic Macrovascular Disease J:174983.
|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
When maintaining a live colony, these mice are bred as heterozygous for the Akita mutation and homozygous for the LDLR mutation.
|Please inquire about possible genotypes.|
The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided,
their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of
each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders
are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in
order to provide the minimum number of animals, animals will ship within 25 weeks.
The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.
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