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. Visit our online Nomenclature tutorial. Mating System Homozygote x Homozygote         (Female x Male)   20-JUL-10 Species laboratory mouse H2 Haplotype b Generation F?+F3 (19-JUL-11) Generation Definitions

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 Ldlr^hlb301 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.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Related Strains

Strains carrying   Ldlr^Hlb301 allele

010814

D2.B6-LdlrHlb301/J

View Strains carrying   Ldlr^Hlb301     (1 strain)

Strains carrying other alleles of Ldlr

007070	AK.129S7(B6)-Ldlrtm1Her/J
006952	B6.129-Akt2tm1.1Mbb Ldlrtm1Her/J
002246	B6.129-Apoetm1Unc Ldlrtm1Her/J
006883	B6.129S7-Ldlrtm1Her Sod2tm1Leb/J
002207	B6.129S7-Ldlrtm1Her/J
006580	B6.Cg-Ins2Akita Ldlrtm1Her/J
006877	B6.Cg-Ldlrtm1Her Tg(H2-K-AKR1B1)1Tj/J
006906	B6.Cg-Lepob Ldlrtm1Her/J
002245	B6;129-Apoetm1Unc Ldlrtm1Her/J
003000	B6;129S-Ldlrtm1Her Apobtm2Sgy/J
002465	B6;129S-Lrpap1tm1Her Ldlrtm1Her/J
002077	B6;129S7-Ldlrtm1Her/J
012845	CBy.129S7(B6)-Ldlrtm1Her/J
007068	D2.129S7(B6)-Ldlrtm1Her/J
010814	D2.B6-LdlrHlb301/J
004192	STOCK Mttptm2Sgy Ldlrtm1Her Apobtm2Sgy Tg(Mx1-cre)1Cgn/J

View Strains carrying other alleles of Ldlr     (16 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

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 provided by MGI

      assigned by genotype

Ldlr^Hlb301/Ldlr⁺

        C57BL/6J-Ldlr^Hlb301/J

• homeostasis/metabolism phenotype
• *normal* homeostasis/metabolism phenotype
  • mice with this mutation do not develop xanthomas when fed a high fat, high cholesterol diet   (MGI Ref ID J:82961)
  • mice with this mutation do not become obese when fed a high fat, high cholesterol diet   (MGI Ref ID J:82961)
• • increased circulating cholesterol level
    • 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   (MGI Ref ID J:82961)
    • 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   (MGI Ref ID J:82961)
  • • increased circulating HDL cholesterol level
      • 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   (MGI Ref ID J:82961)
      • 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   (MGI Ref ID J:82961)
• 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   (MGI Ref ID J:82961)
• hematopoietic system phenotype
• increased macrophage derived foam cell number
  • lesions with foam cell accumulations are seen in coronary arteries   (MGI Ref ID J:82961)
• immune system phenotype
• increased macrophage derived foam cell number
  • lesions with foam cell accumulations are seen in coronary arteries   (MGI Ref ID J:82961)
• cellular phenotype
• increased macrophage derived foam cell number
  • lesions with foam cell accumulations are seen in coronary arteries   (MGI Ref ID J:82961)

Ldlr^Hlb301/Ldlr^Hlb301

        C57BL/6J-Ldlr^Hlb301/J

• homeostasis/metabolism phenotype
• *normal* homeostasis/metabolism phenotype
  • mice with this mutation do not develop xanthomas when fed a high fat, high cholesterol diet   (MGI Ref ID J:82961)
  • mice with this mutation do not become obese when fed a high fat, high cholesterol diet   (MGI Ref ID J:82961)
• • increased circulating cholesterol level
    • 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   (MGI Ref ID J:82961)
    • after 5 weeks on a high fat, high cholesterol diet, 14 week old homozygous mutant mice exhibit dramatically elevated levels of total serum cholesterol   (MGI Ref ID J:82961)
  • • increased circulating HDL cholesterol level
      • 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   (MGI Ref ID J:82961)
      • after 5 weeks on a high fat, high cholesterol diet, 14 week old homozygous mutant mice exhibit greatly elevated HDL cholesterol levels   (MGI Ref ID J:82961)
• 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   (MGI Ref ID J:82961)
• 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   (MGI Ref ID J:82961)
• vision/eye phenotype
• retinal detachment
  • observed in some homozygotes   (MGI Ref ID J:82961)
• hematopoietic system phenotype
• increased macrophage derived foam cell number
  • lesions with foam cell accumulations are seen in coronary arteries   (MGI Ref ID J:82961)
• immune system phenotype
• increased macrophage derived foam cell number
  • lesions with foam cell accumulations are seen in coronary arteries   (MGI Ref ID J:82961)
• cellular phenotype
• increased macrophage derived foam cell number
  • lesions with foam cell accumulations are seen in coronary arteries   (MGI Ref ID J:82961)

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

Ldlr^Hlb301 related

Cardiovascular Research
Hypercholesterolemia

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		LdlrHlb301
Allele Name		heart, lung and blood 301
Allele Type		Chemically induced (ENU)
Common Name(s)		WHC; wicked high cholesterol;
Strain of Origin		C57BL/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

Genotyping Protocols

Ldlr^Hlb301, Pyrosequencing

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

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

Ldlr^Hlb301 related

JAX National Heart, Lung and Blood Program for Genomic Applications (PGA). 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

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice can be bred as homozygotes.
Mating System	Homozygote x Homozygote         (Female x Male)   20-JUL-10
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls

General Supply Notes

• This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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