Strain Name:

C57BL/6J-LdlrHlb301/J

Stock Number:

005061

Availability:

Under Development for Distribution Colony

To register your interest in this strain go to the Strain Interest Form.
Common Names: HLB301;    
Mice homozygous for the "Wicked High Cholesterol" (WHC) mutation develop elevated total cholesterol levels and atherosclerotic lesions when fed an atherogenic diet for 5 weeks. 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). This mutant mouse strain may be useful in studies of familial hypercholesterolemia and atherosclerosis.

Description

Strain Information

Former Names C57BL/6J-Hlb301/J    (Changed: 09-MAY-06 )
HLB-301    (Changed: 29-MAR-06 )
Type Chemically Induced Mutation; Coisogenic; Mutant Strain;
Additional information on Genetically Engineered and Mutant Mice.
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Specieslaboratory mouse
H2 Haplotypeb

Appearance
black
Related Genotype: a/a

Description
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).

This mutant mouse strain may be useful in studies of familial hypercholesterolemia and atherosclerosis.

For additional information on Ldlrhlb301 view the web page on the Mouse Heart, Lung, Blood and Sleep Disorders Center site.

Development
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.

Related Strains

View Strains carrying other alleles of Ldlr     (14 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms
Hypercholesterolemia, Autosomal Dominant - Models with phenotypic similarity to human disease where etiologies involve orthologs.1
1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).
View Mammalian Phenotype Terms

Mammalian Phenotype Terms
      assigned by genotype

LdlrHlb301/Ldlr+

        C57BL/6J-LdlrHlb301/J
  • homeostasis/metabolism phenotype
  • *normal* homeostasis/metabolism phenotype (MGI Ref ID J:82961)
    • mice with this mutation do not develop xanthomas when fed a high fat, high cholesterol diet
    • mice with this mutation do not become obese when fed a high fat, high cholesterol diet
    • increased circulating cholesterol level (MGI Ref ID J:82961)
      • on a chow diet, 14 week old heterozygous mutant female, but not male, mice exhibit significantly (p<=0.05) greater elevation of total serum cholesterol than do C57BL/6J controls
      • after 5 weeks on a high fat, high cholesterol diet, 14 week old heterozygous mutant mice exhibit significantly (p<=0.05) greater elevation of total serum cholesterol than do C57BL/6J control mice; heterozygous G3 female mice (N=4) exhibited, on average, 4.5-fold baseline levels of total cholesterol, versus 2.5-fold baseline for controls
      • increased circulating HDL cholesterol level (MGI Ref ID J:82961)
        • on a chow diet, 14 week old heterozygous mutant female, but not male, mice exhibit significantly (p<=0.05) greater elevation of HDL cholesterol than do C57BL/6J controls
        • after 5 weeks on a high fat, high cholesterol diet, 14 week old heterozygous mutant mice exhibit significantly (p<=0.05) greater elevation of HDL cholesterol than do C57BL/6J control mice
    • increased macrophage derived foam cell number (MGI Ref ID J:82961)
      • lesions with foam cell accumulations are seen in coronary arteries
  • cardiovascular system phenotype
  • increased susceptibility to atherosclerosis (MGI Ref ID J:82961)
    • all mice with this mutation fed an atherogenic diet for 5 weeks develop severe aortic atherosclerosis with collagen deposition, atherosclerosis of the pulmonary arteries, and incipient lesions with foam cell accumulation in the coronary arteries
  • hematopoietic system phenotype
  • increased macrophage derived foam cell number (MGI Ref ID J:82961)
    • lesions with foam cell accumulations are seen in coronary arteries
  • immune system phenotype
  • increased macrophage derived foam cell number (MGI Ref ID J:82961)
    • lesions with foam cell accumulations are seen in coronary arteries

LdlrHlb301/LdlrHlb301

        C57BL/6J-LdlrHlb301/J
  • homeostasis/metabolism phenotype
  • *normal* homeostasis/metabolism phenotype (MGI Ref ID J:82961)
    • mice with this mutation do not develop xanthomas when fed a high fat, high cholesterol diet
    • mice with this mutation do not become obese when fed a high fat, high cholesterol diet
    • increased circulating cholesterol level (MGI Ref ID J:82961)
      • on a chow diet, 14 week old homozygous mutant mice exhibit significantly higher total cholesterol levels than either heterozygous mutants or control C57BL/6J mice
      • after 5 weeks on a high fat, high cholesterol diet, 14 week old homozygous mutant mice exhibit dramatically elevated levels of total serum cholesterol
      • increased circulating HDL cholesterol level (MGI Ref ID J:82961)
        • on a chow diet, 14 week old homozygous mutant mice exhibit significantly higher HDL cholesterol levels than either heterozygous mutants or control C57BL/6J mice
        • after 5 weeks on a high fat, high cholesterol diet, 14 week old homozygous mutant mice exhibit greatly elevated HDL cholesterol levels
    • increased macrophage derived foam cell number (MGI Ref ID J:82961)
      • lesions with foam cell accumulations are seen in coronary arteries
  • cardiovascular system phenotype
  • increased susceptibility to atherosclerosis (MGI Ref ID J:82961)
    • all mice with this mutation fed an atherogenic diet for 5 weeks develop severe aortic atherosclerosis with collagen deposition, atherosclerosis of the pulmonary arteries, and incipient lesions with foam cell accumulation in the coronary arteries
  • liver/biliary system phenotype
  • gallstones (MGI Ref ID J:82961)
    • 14 week old homozygous mutants fed a high fat, high cholesterol diet for 5 weeks have a 50% prevalence of cholesterol gallstones
  • vision/eye phenotype
  • retinal detachment (MGI Ref ID J:82961)
    • observed in some homozygotes
  • hematopoietic system phenotype
  • increased macrophage derived foam cell number (MGI Ref ID J:82961)
    • lesions with foam cell accumulations are seen in coronary arteries
  • immune system phenotype
  • increased macrophage derived foam cell number (MGI Ref ID J:82961)
    • lesions with foam cell accumulations are seen in coronary arteries

LdlrHlb301/?

        C57BL/6J
  • homeostasis/metabolism phenotype
  • increased circulating cholesterol level (MGI Ref ID J:82961)
    • the absolute value for total cholesterol (377 mg/dl) at 13 weeks of age, after consuming the antherogenic diet for > 5 weeks, is within normal range; however, this animal started out with a 4 hour fasted plasma total cholesterol of 88 mg/dl resulting in a 415% increase
View Research Applications

Research Applications
This mouse can be used to support research in many areas including:

Cardiovascular Research
Diet-Induced Atherosclerosis
      Susceptible
Hypercholesterolemia

Internal/Organ Research
Other
      gallstones, jaundice

Mouse/Human Gene Homologs
hypercholesterolemia, familial

LdlrHlb301 related

Cardiovascular Research
Hypercholesterolemia

Genes & Alleles

Gene & Allele Information

 
Allele Symbol LdlrHlb301
Allele Name heart, lung and blood 301
Allele Type Chemically induced (ENU)
Common Name(s) WHC; wicked high cholesterol;
Strain of OriginC57BL/6J
Gene Symbol and Name Ldlr, low density lipoprotein receptor
Chromosome 9
Gene Common Name(s) FH; FHC; LDLCQ2; LDLRA;
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. [MGI Ref ID J:140060]

Genotyping

Genotyping Information

This strain will not have a genotyping protocol or one is not currently available.

Helpful Links

Genotyping resources and troubleshooting

References

References

Selected Reference(s)

Svenson KL; Ahituv N; Durgin RS; Savage H; Magnani PA; Foreman O; Paigen B; Peters LL. 2008. A new mouse mutant for the LDL receptor identified using ENU mutagenesis. J Lipid Res 49(11):2452-62. [PubMed: 18632552]  [MGI Ref ID J:140060]

Additional References

LdlrHlb301 related

JAX National Heart, Lung and Blood Program for Genomic Applications (PGA) URL: http://pga.jax.org. 2003. Heritable mouse mutants from the JAX NHLBI ENU Mutagenesis Program MGI Direct Data Submission :.  [MGI Ref ID J:82961]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & HusbandryWhen maintaining a live colony, these mice can be bred as homozygotes.

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

 

This strain is currently Under Development for Production.
To register your interest in this strain go to the Strain Interest Form.

Estimated Available for Sale Date:

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