STOCK Scarb1^tm1.1Okoch Ldlr^tm1Her/J

Stock number: 033709
Product name: SR-BI^ΔCT/LDLR KO
Research areas: Cardiovascular Research, Metabolism Research, Mouse/Human Gene Homologs

Description

SR-BIΔCT/LDLR KO mice produce a truncated SCARB1 protein and truncated non-functional LDLR protein - making these mice useful when studying coronary heart disease.

Detailed description

SR-BIΔCT/LDLR KO mice produce truncated SCARB1 and truncated non-functional LDLR protein. Double homozygous mice are viable and fertile when maintained on a normal chow diet. When fed an atherogenic (Paigen) diet starting at 6 weeks of age, these mice exhibit cardiac pathologies including rapid onset and fatal, occlusive coronary arterial atherosclerosis, myocardial infarction and premature death (median age of death: 9 weeks). When fed a Western-type atherogenic diet the mice exhibit major adverse cardiovascular events, including spontaneous plaque rupture with MI and stroke and premature death (>80% mortality after 26 weeks). Thus, these mice are useful for studying coronary heart disease and stroke.

The SR-BIΔCT allele contains a point mutation at amino acid 507 which introduces a premature stop codon within the carboxy terminal in exon 12 of the scavenger receptor class B, member 1 (Scarb1) gene. This mutation produces a truncated protein that is missing 3 C-terminal amino acids (⁵⁰⁷AKL⁵⁰⁹). The steady state levels of this truncated protein in the liver are very low relative to the levels of the full-length protein in wildtype mice. Residual levels of receptor protein in the adrenal glands, ovaries, and testes appears sufficient to maintain nearly normal cholesteryl ester (CE) stores. Mice singly homozygous for the SR-BIΔCT allele are viable and fertile and have hypercholesterolemia.

Mice singly homozygous for the Ldlr^tm1Her mutation have an elevated serum cholesterol level of 200-400 mg/dl and they have very high levels (>2,000 mg/dl) when fed a high fat diet. Normal serum cholesterol in the mouse is 80-100 mg/dl.

The SR-BIΔCT/LDLR KO mice (Stock No. 033709) was assembled by breeding Stock No. 032062 to Stock No. 002207. In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. It should be noted that the phenotype of these mice could vary from that originally described. We may modify the strain description if necessary as published results become available.

Development

A targeting construct was designed to insert a point mutation in exon 12 of the scavenger receptor class B, member 1 (Scarb1) gene, and a frt-flanked neomycin resistance (neo) cassette was inserted downstream of exon 12. The point mutation at amino acid 507 results in an alanine change to a stop codon. This targeting construct was electroporated into (C57BL/6NTac x 129S6/SvEvTac)F1-derived iTL BA1 embryonic stem (ES) cells and correctly targeted ES cells were injected into blastocysts. The resulting chimeric mice were bred to mice expressing FLP-recombinase on a C57BL/6 background to remove the neo cassette. SR-BIΔCT (Srb1^deltaCT) mice, lacking the neo cassette, were bred to 129S2/SvPasCrl mice and were further maintained on a mixed genetic background as Stock No. 032062.

Some of these SR-BIΔCT mice were bred to LDLR KO mice (Stock No. 002207) that have a neo cassette inserted into exon 4, resulting in a truncated non-functional LDLR protein. The resulting SR-BIΔCT/LDLR KO mice are available on a mixed genetic background as this Stock No. 033709.

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; Ldlr^-
Marker symbol: Ldlr
Marker name: low density lipoprotein receptor
Marker synonyms: 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.

Allele

Symbol: Scarb1^tm1.1Okoch
Name: targeted mutation 1.1, Olivier Kocher
MGI accession ID: MGI:6158932
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: Srb1^deltaCT; SR-BIdeltaCT
Marker symbol: Scarb1
Marker name: scavenger receptor class B, member 1
Marker synonyms: Cd36l1; Chohd1; CLA1; Cla-1; D5Ertd460e; HDLCQ6; Hdlq1; HDLQTL6; Hlb398; Srb1; SR-B1; SRBI; SR-BI
Chromosome: 5
Strain of origin: (C57BL/6NTac x 129S6/SvEvTac)F1
Molecular note: The targeting construct is designed to insert a point mutation in exon 12, and an FRT-flanked neomycin resistance (neo) cassette downstream of exon 12. The point mutation at amino acid 507 results in an alanine change to a stop codon. Flp-mediated recombination removed the FRT-flanked neo cassette.