B6;129S-Ldlrap1^tm1Her/J

Stock number: 005212
Product name: Arh-
Research areas: Cardiovascular Research

Description

These Ldlrap1 (formerly Ahr) knock-out mice exhibit elevated low density lipoproteins (LDL) plasma levels, and analysis of liver tissue reveals abnormal LDL receptor (LDLR ) localization to the sinsusoidal membrane.

Detailed description

Mice that are homozygous for the targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. No gene product (protein) is detected by Western blot analysis of liver tissue. Low density lipoproteins (LDL) plasma levels are elevated in homozygous mutant mice. Mice homozygous for the mutant allele exhibit mild hypercholesterolemia when fed a chow diet. Low density lipoprotein-cholesterol, LDL-C, plasma levels are elevated 11 fold when homozygous mutant mice are fed the Paigen high cholesterol diet (1.25% cholesterol, 7.5% cocoa butter, 7.5% casein, 0.5% cholic acid) and 4.7 fold when fed the Western diet (0.2% cholesterol). The circulation clearance rate of radiolabeled LDL is reduced by half in mice homozygous for the mutant allele. Immunofluorescence microscopic analysis of liver tissue reveals abnormal LDLR localization to the sinsusoidal membrane. This mutant mouse strain may be useful in studies of autosomal recessive hypercholesterolemia.

Development

A targeting vector containing a loxP and FRT site flanked neomycin resistance gene and 2 tandemly arranged herpes simplex virus thymidine kinase genes was used to disrupt exon 4. The construct was electroporated into 129S6/SvEvTac derived SM1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to C57BL/6 mice. Heterozygote were bred to generate homozygotes.

Allele

Symbol: Ldlrap1^tm1Her
Name: targeted mutation 1, Joachim Herz
MGI accession ID: MGI:2670480
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Ldlrap1
Marker name: low density lipoprotein receptor adaptor protein 1
Chromosome: 4
Strain of origin: 129S6/SvEvTac
Molecular note: Exon 4 was replaced with a neomycin selection cassette that was flanked by both loxP and FRT sites. The deletion of exon 4 disrupts sequence encoding the PTB domain. Normal protein was undetected in homozygous mutant mice by Western blot analysis using an antibody directed against the PTB domain. If aberrant splicing were to occur between exons 3 and 5, a frameshift mutation and resultant nonsense mutation would putatively preclude the translation of the clathrin and adapter protein complex (AP-2) binding sites.