Ldlr<Hlb301> Chemically induced Allele Detail MGI Mouse (MGI:2683091)

Ldlr^Hlb301
Chemically induced Allele Detail

Nomenclature

Symbol:	Ldlr^Hlb301
Name:	low density lipoprotein receptor; heart, lung and blood 301
MGI ID:	MGI:2683091
Synonyms:	WHC, wicked high cholesterol
Gene:	Ldlr Location: Chr9:21528038-21554360 bp, + strand Genetic Position: Chr9, 5.0 cM

Mutation
origin

Strain of Origin:

C57BL/6J

Mutation
description

Allele Type:	Chemically induced (ENU)
Mutation:	Single point mutation
	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. (J:140060)
Inheritance:	Semidominant

Find Mice (IMSR)

Mouse strains and cell lines available from the International Mouse Strain Resource (IMSR)

Carrying this Mutation:	Mouse Strains: 2 strains available Cell Lines: 0 lines available
Carrying any Ldlr Mutation:	33 strains or lines available

Phenotype
summary

Phenotype Summary by Mammalian Phenotype terms

(show or hide all annotated terms)

Genotypes are listed in the next section.

Key:

hm	homozygous	ht	heterozygous
cn	conditional genotype	cx	complex: > 1 genome feature
tg	involves transgenes	ot	other: hemizygous, indeterminate,...
N	normal phenotype		expected model not found

Affected Systems	Genotypes:	hm1	ht2	ot3
cardiovascular system		√	√
increased susceptibility to atherosclerosis		√	√
		hm1	ht2	ot3
hematopoietic system		√	√
increased macrophage derived foam cell number		√	√
		hm1	ht2	ot3
homeostasis/metabolism		√	√	√
homeostasis/metabolism phenotype		N	N
increased macrophage derived foam cell number		√	√
increased circulating cholesterol level		√	√	√
increased circulating HDL cholesterol level		√	√
		hm1	ht2	ot3
immune system		√	√
increased macrophage derived foam cell number		√	√
		hm1	ht2	ot3
liver/biliary system		√
gallstones		√
		hm1	ht2	ot3
vision/eye		√
retinal detachment		√

		hm1	ht2	ot3
Disease Models		√	√
Hypercholesterolemia, Autosomal Dominant		√	√

Phenotypic
data by
genotype

Phenotypic Data by Genotype

(show or hide all phenotypic details)

Genotype

Allelic Composition

Genetic Background

hm1 Disease Model

Ldlr^Hlb301/Ldlr^Hlb301

C57BL/6J-Ldlr^Hlb301/J

homeostasis/metabolismhomeostasis/metabolism phenotype (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 macrophage derived foam cell number (J:82961)

lesions with foam cell accumulations are seen in coronary arteries

increased circulating cholesterol level (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 (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

cardiovascular systemincreased susceptibility to atherosclerosis (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 systemgallstones (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/eyeretinal detachment (J:82961)

observed in some homozygotes

hematopoietic systemincreased macrophage derived foam cell number (J:82961)

lesions with foam cell accumulations are seen in coronary arteries

immune systemincreased macrophage derived foam cell number (J:82961)

lesions with foam cell accumulations are seen in coronary arteries

Mouse Models of Human Disease	Note	Ref(s)
Models with phenotypic similarity to human diseases associated with human LDLR.
Hypercholesterolemia, Autosomal Dominant		J:82961

ht2 Disease Model

Ldlr^Hlb301/Ldlr⁺

C57BL/6J-Ldlr^Hlb301/J

homeostasis/metabolismhomeostasis/metabolism phenotype (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 macrophage derived foam cell number (J:82961)

lesions with foam cell accumulations are seen in coronary arteries

increased circulating cholesterol level (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 (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

cardiovascular systemincreased susceptibility to atherosclerosis (J:82961)

hematopoietic systemincreased macrophage derived foam cell number (J:82961)

lesions with foam cell accumulations are seen in coronary arteries

immune systemincreased macrophage derived foam cell number (J:82961)

lesions with foam cell accumulations are seen in coronary arteries

Mouse Models of Human Disease	Note	Ref(s)
Models with phenotypic similarity to human diseases associated with human LDLR.
Hypercholesterolemia, Autosomal Dominant		J:82961

ot3

Ldlr^Hlb301/?

C57BL/6J

Disease
models

Mouse Models of Human Disease	Note	Genotype			Ref(s)
			Allelic Composition	Genetic Background
Models with phenotypic similarity to human diseases associated with human LDLR.
Hypercholesterolemia, Autosomal Dominant OMIM ID: 143890		ht2	Ldlr^Hlb301/Ldlr⁺	C57BL/6J-Ldlr^Hlb301/J	J:82961
		hm1	Ldlr^Hlb301/Ldlr^Hlb301	C57BL/6J-Ldlr^Hlb301/J	J:82961

Notes

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).

References

Original:	J:82961 JAX National Heart, Lung and Blood Program for Genomic Applications (PGA) URL: http://pga.jax.org, "Heritable mouse mutants from the JAX NHLBI ENU Mutagenesis Program" MGI Direct Data Submission 2003-8;():
All:	2 reference(s)

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