B6.129S7-Ldlr^tm1Her Sod2^tm1Leb/J

Stock number: 006883
Product name: LDLR-
Strain synonyms: LDLR MnSOD
Research areas: Cardiovascular Research, Developmental Biology Research, Diabetes and Obesity Research, Metabolism Research, Mouse/Human Gene Homologs, Neurobiology Research, Research Tools

Description

Mice heterozygous for Sod2^tm1Leb and homozygous for Ldlr^tm1Her may be predisposed to atherosclerosis.

Detailed description

Independently, mice that are homozygous for this MnSOD mutation (Sod2^tm1Leb) allele exhibit postnatal lethality and exhibit anemia, degeneration of neurons in the basal ganglia and brainstem, progressive motor disturbances, and myocardial injury. Individual LDLR homozygous mutants are predisposed to atherosclerosis. When mutant mice are homozygous for both alleles, they die in utero. Mice heterozygous for the Sod2 mutation and homozygous for the LDLR are viable and fertile. The mice may be useful in studies of diabetes, metabolism, hyperglycemia, atherosclerosis, and 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 Sod2^tm1Leb was created by Dr. Russell Lebovitz (Baylor College of Medicine) by replacing exons 1-2 with a PGK-HPRT minigene. The targeting vector was electroporated into 129S7/SvEvBrd-derived AB2.1 and then maintained on a congenic genetic background at The Jackson Laboratory (Stock No. 002973). To generate the double mutant strain, Stock No. 002207 mice were bred with Stock No. 002973 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 D17Mit143.2.

Allele

Symbol: Sod2^tm1Leb
Name: targeted mutation 1, Russell M Lebovitz
MGI accession ID: MGI:1857480
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Sod2
Marker name: superoxide dismutase 2, mitochondrial
Chromosome: 17
Strain of origin: 129S7/SvEvBrd-Hprt^b-m2
Molecular note: A human HPRT minigene driven by the PGK promoter replaced exons 1 and 2, and sequences approximately 500 bp immediately 5' of exon 1. The replaced region encodes the transcription and translation start sites, the mitochondrial targeting sequence, and one of three histidines that bind directly to the manganese cofactor. Northern blot analysis of brain did not detect mRNA in homozygous mutant mice. Enzyme activity assays of heart did not detect active protein in homozygous mutant mice.

Allele

Symbol: Ldlr^tm1Her
Name: targeted mutation 1, Joachim Herz
MGI accession ID: MGI:1857212
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Ldlr
Marker name: low density lipoprotein receptor
Chromosome: 9
Strain of origin: 129S7/SvEvBrd-Hprt⁺
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.