B6.Cg-Ins2^Akita Ldlr^tm1Her/J

Stock number: 006580
Product name: Akita LDLR KO
Research areas: Cardiovascular Research, Cell Biology Research, Diabetes and Obesity Research, Endocrine Deficiency Research, Metabolism Research, Mouse/Human Gene Homologs, Research Tools

Description

These double mutant mice carry the Akita mutation, characterized by early-onset NIDDM, and an Ldlr knock-out, characterized by increased plasma cholesterol levels.

Detailed description

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.

Development

The Ldlr^tm1Her 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

Symbol: Ins2^Akita
Name: Akita
MGI accession ID: MGI:1857572
Generation method: Spontaneous
Synonyms: Akita; Akita^Ins2; Ins2^C96Y; Ins2^Mody; Mody; Mody4
Marker symbol: Ins2
Marker name: insulin II
Marker synonyms: CP-II; IDDM; IDDM1; IDDM2; ILPR; Ins-2; InsII; IRDN; Mody; MODY10; Mody4; PNDM4
Chromosome: 7
Strain of origin: C57BL/6NSlc
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.

Allele

Symbol: Ldlr^tm1Her
Name: targeted mutation 1, Joachim Herz
MGI accession ID: MGI:1857212
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: LDLR-; LDLR KO; LDLr0; LDLrKO; LDLr-KO; Ldlrtm1Her
Marker symbol: Ldlr
Marker name: low density lipoprotein receptor
Marker synonyms: FH; FHC; FHCL1; LDLCQ2; LDLRA
Chromosome: 9
Strain of origin: 129S7/SvEvBrd-Hprt1⁺
Site of expression: Immunoblot analysis of liver membranes detected a truncated protein in homozygous mutant animals.
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.
General note: When used in bone marrow transplant into Ldlr^tm1Her homozygous mice, Abca1^tm1Jdm Abcg1^tm1Dgen 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.