Overview

Also Known As:HLB301, WHC

The single point mutation (Ldlr^Hlb301) in this ENU mutagenized strain was originally named "Wicked High Cholesterol" (WHC) for a phenotype of elevated atherosclerotic lesion formations and reduced hepatosteatosis following an atherogenic diet. This mutant mouse strain may be useful in studies of familial hypercholesterolemia and atherosclerosis.

Genetic overview

Genetic Background	Generation

Ldlr^Hlb301

Allele Type	Gene Symbol	Gene Name
Chemically induced (ENU)	Ldlr	low density lipoprotein receptor

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Research Applications

Internal/Organ Research
Cardiovascular Research
Mouse/Human Gene Homologs

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed 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.

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.

Control Suggestions

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

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):2452-62PubMed: 18632552 MGI: J:140060

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Genetics

Ldlr^Hlb301

Allele Symbol: Ldlr^Hlb301

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
Gene Synonym(s)
Strain of Origin	C57BL/6J
Chromosome	9
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.

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

familial hypercholesterolemia

Research Areas By Phenotype

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

Internal/Organ Research
- Other
  - gallstones, jaundice
Cardiovascular Research
- Hypercholesterolemia
- Diet-Induced Atherosclerosis
  - Susceptible
Mouse/Human Gene Homologs
- hypercholesterolemia, familial

Genotype: Ldlr^Hlb301 related

Cardiovascular Research
- Hypercholesterolemia

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

Genotype: Ldlr^Hlb301/Ldlr^Hlb301
C57BL/6J-Ldlr/J

cardiovascular system phenotype

increased susceptibility to atherosclerosis
- 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

mammalian phenotype

homeostasis/metabolism phenotype
- Normal - mice with this mutation do not become obese when fed a high fat, high cholesterol diet
- Normal - mice with this mutation do not develop xanthomas when fed a high fat, high cholesterol diet

vision/eye phenotype

retinal detachment
- observed in some homozygotes

cellular phenotype

increased macrophage derived foam cell number
- lesions with foam cell accumulations are seen in coronary arteries

hematopoietic system phenotype

increased macrophage derived foam cell number
- lesions with foam cell accumulations are seen in coronary arteries

homeostasis/metabolism phenotype

increased circulating cholesterol level
- after 5 weeks on a high fat, high cholesterol diet, 14 week old homozygous mutant mice exhibit dramatically elevated levels of total serum cholesterol
- 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

increased circulating HDL cholesterol level
- after 5 weeks on a high fat, high cholesterol diet, 14 week old homozygous mutant mice exhibit greatly elevated HDL cholesterol levels
- 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

immune system phenotype

increased macrophage derived foam cell number
- lesions with foam cell accumulations are seen in coronary arteries

liver/biliary system phenotype

gallstones
- 14 week old homozygous mutants fed a high fat, high cholesterol diet for 5 weeks have a 50% prevalence of cholesterol gallstones

Genotype: Ldlr^Hlb301/Ldlr⁺
C57BL/6J-Ldlr/J

cardiovascular system phenotype

increased susceptibility to atherosclerosis
- 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

mammalian phenotype

homeostasis/metabolism phenotype
- Normal - mice with this mutation do not become obese when fed a high fat, high cholesterol diet
- Normal - mice with this mutation do not develop xanthomas when fed a high fat, high cholesterol diet

cellular phenotype

increased macrophage derived foam cell number
- lesions with foam cell accumulations are seen in coronary arteries

hematopoietic system phenotype

increased macrophage derived foam cell number
- lesions with foam cell accumulations are seen in coronary arteries

homeostasis/metabolism phenotype

increased circulating cholesterol level
- .5-fold baseline levels of total cholesterol, versus 2.5-fold baseline for 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
- 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

increased circulating HDL cholesterol level
- 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
- 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

immune system phenotype

increased macrophage derived foam cell number
- lesions with foam cell accumulations are seen in coronary arteries

References

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):2452-62PubMed: 18632552 MGI: J:140060

Additional References

Rodionov RN; Begmatov H; Jarzebska N; Patel K; Mills MT; Ghani Z; Khakshour D; Tamboli P; Patel MN; Abdalla M; Assaf M; Bornstein SR; Millan JL; Bode-Boger SM; Martens-Lobenhoffer J; Weiss N; Savinova OV. 2019. Homoarginine Supplementation Prevents Left Ventricular Dilatation and Preserves Systolic Function in a Model of Coronary Artery Disease. J Am Heart Assoc 8(14):e012486PubMed: 31304837 MGI: J:286011

Additional - Ldlr^Hlb301 related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Pyrosequencing:Ldlr
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, these mice can be bred as homozygotes.
- Additional Breeding and Husbandry Support
Appearance
- black
  Related Genotype: a/a
Citation
When using the WHC mouse strain in a publication, please cite the originating article(s) and include JAX stock #005061 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Homozygous for Ldlr<Hlb301>, 1 pair minimum

Related Products and Services

Frozen Mouse Embryo	C57BL/6J-Ldlr<Hlb301>/J Frozen Embryos	$2595.00
Frozen Mouse Embryo	C57BL/6J-Ldlr<Hlb301>/J Frozen Embryos	$2595.00
Frozen Mouse Embryo	C57BL/6J-Ldlr<Hlb301>/J Frozen Embryos	$3373.50
Frozen Mouse Embryo	C57BL/6J-Ldlr<Hlb301>/J Frozen Embryos	$3373.50

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Also Known As:HLB301, WHC

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

LdlrHlb301

Allele Symbol: LdlrHlb301

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Research Areas By Phenotype

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

Genotype: LdlrHlb301 related

Mammalian Phenotype Terms by Genotype

Genotype: LdlrHlb301/LdlrHlb301C57BL/6J-Ldlr/J

cardiovascular system phenotype

mammalian phenotype

vision/eye phenotype

cellular phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

immune system phenotype

liver/biliary system phenotype

Genotype: LdlrHlb301/Ldlr+C57BL/6J-Ldlr/J

cardiovascular system phenotype

mammalian phenotype

cellular phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

immune system phenotype

References

Additional References

Additional - LdlrHlb301 related

Genotyping Protocols

Breeding Considerations

Appearance

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Ldlr^Hlb301

Allele Symbol: Ldlr^Hlb301

Genotype: Ldlr^Hlb301 related

Genotype: Ldlr^Hlb301/Ldlr^Hlb301
C57BL/6J-Ldlr/J

Genotype: Ldlr^Hlb301/Ldlr⁺
C57BL/6J-Ldlr/J

Additional - Ldlr^Hlb301 related