B6.Cg-Ldlr^tm1Her Tg(H2-K-AKR1B1)1Tj/J

Stock number: 006877
Product name: huARtg LDLR
Research areas: Cardiovascular Research, Diabetes and Obesity Research, Metabolism Research, Mouse/Human Gene Homologs, Research Tools

Description

Mice that are hemizygous for the transgene and homozygous for the Ldlr^tm1Her knock-out mutation are predisposed to atherosclerosis and hypercholesterolemia.

Detailed description

Independently, mice hemizygous for this "huAR" transgene express human aldose reductase as a model for increased oxidative stress, while LDLR homozygotes are predisposed to atherosclerosis and hypercholesterolemia. The donating investigators report that the H2-K^d promoter functions on this H2-K^b genetic background without any loss of transgene expression. When mutant mice are hemizygous for the transgene and homozygous for the targeted allele, they may be useful in studies of diabetes, metabolism, atherosclerosis, hypercholesterolemia, and oxidative stress.

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 "huAR" transgene was created by Dr. Yamaoka and colleagues (University of Tokushima) by placing a human aldose reductase (AKR1B1) cDNA under the control of the murine H2-K^d MHC class I promoter. A single male was used to generate transgenic mice on a mixed C57BL/6;DBA/2 genetic background. Transgenic mice were then sent to Dr. Eva Feldman (University of Michigan). From there, mice on a mixed (approximately 80% C57BL/6J) background were shipped to Dr. Jan Breslow at The Rockefeller University. To generate the double mutant strain, Stock No. 002207 mice were bred with the huAR transgenic mice in the laboratory of Dr. Breslow. 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 si ngle exception is D5Mit314. The Y chromosome may not have been fixed to the C57BL/6J genetic background.

Allele

Symbol: Tg(H2-K-AKR1B1)1Tj
Name: transgene insertion 1, University of Tokushima School of Medicine
MGI accession ID: MGI:3703741
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: hAR-Tg
Marker symbol: Tg(H2-K-AKR1B1)1Tj
Marker name: transgene insertion 1, University of Tokushima School of Medicine
Marker synonyms: hAR-Tg
Chromosome: UN
Strain of origin: (C57BL/6 x DBA/2)F1
Expressed genes: AKR1B1,aldo-keto reductase family 1 member B,human
Molecular note: Expression of the full length human aldose reductase (AKR1B1) cDNA is under control of the murine H2-K^d promoter. Northern and Wester blotting shows expression of human aldose reductase mRNA and protein in all tissues tested.

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.