Mice homozygous for the ENU induced low density lipoprotein receptor mutation (commonly called "Wicked High Cholesterol") develop elevated total cholesterol levels and atherosclerotic lesions after an atherogenic diet. This mutant mouse strain may be useful in studies of familial hypercholesterolemia and atherosclerosis.
The Jackson Laboratory
Mice that are homozygous for the mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. This single base pair G to A transition mutation in exon 14, nucleotide 2096 was induced by ENU mutagenesis. The "Wicked High Cholesterol" (WHC) phenotype was mapped to the Ldlr, low density lipoprotein receptor, gene. Although total plasma cholesterol levels do not differ between sexes, when fed a standard chow diet for 5 weeks, homozygous WHC males exhibit higher triglyceride and HDL levels than homozygous WHC females. When fed Western diet for 5 weeks, mutant WHC males exhibit higher HDL levels than female WHC mutants. When fed an atherogenic diet for 5 weeks, WHC homozygotes of both sexes develop elevated total cholesterol levels of more than a 4 fold increase when compared to WHC homozygotes on standard chow diet. Cholesterol and HDL levels of WHC homozygotes fed atherogenic diet for 5 weeks remain elevated 1 month after resuming chow diet. Atherosclerotic lesions develop in WHC homozygotes fed Western and atherogenic diet, with the largest lesions observed in homozygous WHC mice fed the atherogenic diet. Long term (34 weeks) atherogenic diet consumption results in formation of multiple cutaneous xanthomas in the distal limbs of WHC homozygotes, 42 weeks of age. Half of the WHC homozygotes develop gallstones.
On the atherogenic diet WHC homozygotes develop significantly greater HDL and triglyceride levels, as well as larger atherosclerotic lesions, when compared to mice carrying the Ldlr targeted mutation (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. This is the case for the strain above. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.
Following multidose ethylnitrosourea (ENU) treatments to induce mutations in male founder C57BL/6J mice (Stock No. 000664), a forward genetic screen was utilized to identify phenotypic deviants in complex heart, lung, blood, and sleep disorders, at the Mouse Heart, Lung, Blood, and Sleep Disorders (HLBS) Center at The Jackson Laboratory.
Screening of third generation mice (G3) identified mice with elevated total plasma cholesterol levels after being fed an atherogenic diet for 5 weeks. The "Wicked High Cholesterol" (WHC) phenotype was mapped to chromosome 9. Sequencing of the candidate gene Ldlr, low density lipoprotein receptor, revealed a G to A transition in exon 14, nucleotide 2096; missense mutation C699Y. Heterozygotes were crossed to generate homozygotes. The mice have been maintained on a C57BL/6J background and then backcrossed to DBA/2J (Stock No. 000671), for at least 9 generations.
|Allele Name||heart, lung and blood 301|
|Allele Type||Chemically induced (ENU)|
|Allele Synonym(s)||WHC; wicked high cholesterol|
|Gene Symbol and Name||Ldlr, low density lipoprotein receptor|
|Strain of Origin||C57BL/6J|
|General Note||Schmidt and Kostner (Atherosclerosis 148(2):431-432, 1999) identified the same mutation in an Austrian patient with Familial Hypercholesterolemia (FH): a G-to-A transition at nucleotide 2093 of the human LDLR coding sequence, resulting in replacement of cysteine with tyrosine at amino acid 677 (count does not include 21-aa signal peptide).|
|Molecular Note||This phenotypic mutation was identified in a screen of the progeny of ENU treated male mice for serum cholesterol elevation in response to a high fat, high cholesterol diet. It is a G to A transition at nucleotide 2096 of the mouse cDNA sequence, in a region encoded by exon 14, resulting in replacement of a highly conserved cysteine by tyrosine at amino acid 699 (C699Y; count includes 21-aa signal peptide), which is predicted to cause a folding defect and failure of the protein to transit from the endoplasmic reticulum to the Golgi system.|
When maintaining a live colony, these mice can be bred as homozygotes.
When using the D2.B6-LdlrHlb301/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #010814 in your Materials and Methods section.
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