Phenotypes associated with this allele

• Allele Symbol: Nr1h3^tm1Djm
• Allele Name: targeted mutation 1, David J Mangelsdorf
• Allele ID: MGI:2181380
• Summary: 5 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Nr1h3^tm1Djm/Nr1h3^tm1Djm	involves: 129S6/SvEvTac * C57BL/6	MGI:4358795
cn2	Nr1h3^tm1Djm/Nr1h3^tm1Djm Nus1^tm1.1Qrm/Nus1^tm1.1Qrm Speer6-ps1^Tg(Alb-cre)21Mgn/Speer6-ps1^+	involves: 129 * C57BL/6 * DBA * SJL	MGI:6106901
cx3	Nr1h2^tm1Djm/Nr1h2^tm1Djm Nr1h3^tm1Djm/Nr1h3^tm1Djm	involves: 129S6/SvEvTac	MGI:4358870
cx4	Nr1h3^tm1Djm/Nr1h3^tm1Djm Tg(APPswe,PSEN1dE9)85Dbo/0	involves: 129S6/SvEvTac * C3H * C57BL/6	MGI:4359165
cx5	Nr1h2^tm1Djm/Nr1h2^tm1Djm Nr1h3^tm1Djm/Nr1h3^tm1Djm	involves: 129S6/SvEvTac * C57BL/6	MGI:4358884

Genotype
MGI:4358795

hm1

• Allelic Composition: Nr1h3^tm1Djm/Nr1h3^tm1Djm
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

growth/size/body

enlarged ovary ( J:158168 )

♀ • following superovulation protocols, ovary size is increased compared with ovaries from similarly treated wild-type mice

♀ • however, estradiol-treated mice have normal sized ovaries

ovary cyst ( J:158168 )

♀ • superovulated-mice exhibit hemorrhagic cysts unlike similarly treated wild-type mice

increased liver weight ( J:47971 )

• 3 months on a high cholesterol diet leads to a doubling in liver mass without increasing body weight

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:81696 )

• mice succumb to infection of Listeria monocytogenes 2-3 days earlier than controls

reproductive system

increased male germ cell apoptosis ( J:120913 )

♂ • apoptosis of germ cells within seminiferous tubules is more than double that of controls

abnormal corpus luteum morphology ( J:158168 )

♀ • superovulated-mice rarely exhibit hemorrhage of the corpus luteum unlike similarly treated wild-type mice

enlarged ovary ( J:158168 )

♀ • following superovulation protocols, ovary size is increased compared with ovaries from similarly treated wild-type mice

♀ • however, estradiol-treated mice have normal sized ovaries

ovary cyst ( J:158168 )

♀ • superovulated-mice exhibit hemorrhagic cysts unlike similarly treated wild-type mice

abnormal ovary physiology ( J:158168 )

♀ • following follicle retrieval, a greater number of follicles are expulsed with 45% dead oocytes or empty zonae pellucidae unlike in similarly treated wild-type mice

ovary hemorrhage ( J:158168 )

♀ • superovulated-mice rarely exhibit hemorrhage of the corpus luteum unlike similarly treated wild-type mice

abnormal superovulation ( J:158168 )

♀ • superovulated-mice exhibit increased follicle expulsion, increased number of dead oocytes or empty zona pellucida, enlarged ovaries, ovarian cysts, rare ovarian hemorrhage, increased ovarian vascular permeability, circulating estradiol, and inflammation compared with similarly treated wild-type mice

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:243753 )

♀N • when fed Western diet

♀N • circulating triglyceride level

♀N • liver triglyceride level

♀N • circulating free fatty acid level

♀N • liver free fatty acid level

♀N • circulating cholesterol level both total and free

decreased circulating testosterone level ( J:120913 )

• testosterone production in the testes is significantly reduced compared to controls

increased circulating estradiol level ( J:158168 )

• superovulated-mice compared to in similarly treated wild-type

decreased circulating luteinizing hormone level ( J:120913 )

• plasma LH levels are almost half that of controls

increased circulating cholesterol level ( J:47971 )

• there is a 15- to 20- fold increase in liver cholesterol levels 7 days after being switched to a high (2%) cholesterol diet while only a modest increase is observed in control mice

• when fed an intermediate (0.2%) cholesterol diet, mice have increases of 3- and 10- fold after 7 and 22 days on the diet

increased circulating LDL cholesterol level ( J:47971 )

• serum LDL levels are increased 5-fold in mice that are fed a high cholesterol diet

increased circulating alanine transaminase level ( J:47971 )

• serum alanine transaminase levels are increased in mice that are fed a high cholesterol diet

increased circulating aspartate transaminase level ( J:47971 )

• serum aspartate transaminase levels are increased in mice that are fed a high cholesterol diet

increased erythrocyte sedimentation rate ( J:158168 )

• following superovulation protocols, mice exhibit an increase in blood sediment rate compared with wild-type mice indicating inflammation

abnormal bile salt homeostasis ( J:47971 )

• mice fail to increase their pool of bile acid in response to a high cholesterol diet as wild-type mice do

• less fecal excretion of bile acid occurs in mice fed the high cholesterol diet compared to control mice

• the ratio of cholic acid to muricholic acid within the bile acid pool is significantly higher than controls on a chow-fed diet, and does not decrease when fed a high cholesterol diet

increased liver cholesterol level ( J:47971 , J:243753 )

• there is a 15- to 20- fold increase in liver cholesterol levels 7 days after being switched to a high (2%) cholesterol diet while only a modest increase is observed in control mice (J:47971)

• when fed an intermediate (0.2%) cholesterol diet, mice have increases of 3- and 10- fold after 7 and 22 days on the diet (J:47971)

♀ • both total and free when fed Western diet (J:243753)

liver/biliary system

increased liver weight ( J:47971 )

• 3 months on a high cholesterol diet leads to a doubling in liver mass without increasing body weight

increased liver cholesterol level ( J:47971 , J:243753 )

• there is a 15- to 20- fold increase in liver cholesterol levels 7 days after being switched to a high (2%) cholesterol diet while only a modest increase is observed in control mice (J:47971)

• when fed an intermediate (0.2%) cholesterol diet, mice have increases of 3- and 10- fold after 7 and 22 days on the diet (J:47971)

♀ • both total and free when fed Western diet (J:243753)

hepatic steatosis ( J:47971 )

• on high (2%) cholesterol diets, livers develop fatty deposits that increase in number and size with time while control mice exhibit no abnormalities

• the liver appears pale and is double in size, inflammatory foci are developing, and signs of liver degeneration are evident after 3 months on the diet

liver degeneration ( J:47971 )

• signs of liver degeneration are evident after 3 months on a high cholesterol diet

• increased serum levels of alanine and aspartate amino transferases are also indicitave of liver injury

• hepatocytes have lost most of their normal cell structure after 90 days on a high cholesterol diet

pale liver ( J:47971 )

• liver appears white after 3 months on a high cholesterol diet due to presence of cholesterol filled droplets

cardiovascular system

ovary hemorrhage ( J:158168 )

♀ • superovulated-mice rarely exhibit hemorrhage of the corpus luteum unlike similarly treated wild-type mice

increased vascular permeability ( J:158168 )

• in the ovaries of superovulated-mice compared to in similarly treated wild-type

immune system

increased inflammatory response ( J:158168 )

• following superovulation protocols, mice exhibit an increase in blood sediment rate compared with wild-type mice indicating inflammation

increased susceptibility to bacterial infection ( J:81696 )

• mice succumb to infection of Listeria monocytogenes 2-3 days earlier than controls

• bacterial burden in the liver of day 2 of infection is 2 logs higher than controls

endocrine/exocrine glands

abnormal corpus luteum morphology ( J:158168 )

♀ • superovulated-mice rarely exhibit hemorrhage of the corpus luteum unlike similarly treated wild-type mice

enlarged ovary ( J:158168 )

♀ • following superovulation protocols, ovary size is increased compared with ovaries from similarly treated wild-type mice

♀ • however, estradiol-treated mice have normal sized ovaries

ovary cyst ( J:158168 )

♀ • superovulated-mice exhibit hemorrhagic cysts unlike similarly treated wild-type mice

abnormal ovary physiology ( J:158168 )

♀ • following follicle retrieval, a greater number of follicles are expulsed with 45% dead oocytes or empty zonae pellucidae unlike in similarly treated wild-type mice

ovary hemorrhage ( J:158168 )

♀ • superovulated-mice rarely exhibit hemorrhage of the corpus luteum unlike similarly treated wild-type mice

cellular

increased male germ cell apoptosis ( J:120913 )

♂ • apoptosis of germ cells within seminiferous tubules is more than double that of controls

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
ovarian hyperstimulation syndrome		DOID:5425	OMIM:608115	J:158168

Genotype
MGI:6106901

cn2

• Allelic Composition: Nr1h3^tm1Djm/Nr1h3^tm1Djm; Nus1^tm1.1Qrm/Nus1^tm1.1Qrm; Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺
• Genetic Background: involves: 129 * C57BL/6 * DBA * SJL

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:243753 )

♀N • when fed Western diet

♀N • circulating triglyceride level

♀N • liver triglyceride level

♀N • circulating free fatty acid level

♀N • liver free fatty acid level

♀N • circulating cholesterol level both total and free

increased liver cholesterol level ( J:243753 )

♀ • both total and free when fed Western diet

liver/biliary system

increased liver cholesterol level ( J:243753 )

♀ • both total and free when fed Western diet

Genotype
MGI:4358870

cx3

• Allelic Composition: Nr1h2^tm1Djm/Nr1h2^tm1Djm; Nr1h3^tm1Djm/Nr1h3^tm1Djm
• Genetic Background: involves: 129S6/SvEvTac

homeostasis/metabolism

increased liver cholesterol level ( J:64343 )

• hepatic cholesterol levels are 4-fold higher than controls in mice fed a 0.2% cholesterol diet

liver/biliary system

increased liver cholesterol level ( J:64343 )

• hepatic cholesterol levels are 4-fold higher than controls in mice fed a 0.2% cholesterol diet

Genotype
MGI:4359165

cx4

• Allelic Composition: Nr1h3^tm1Djm/Nr1h3^tm1Djm; Tg(APPswe,PSEN1dE9)85Dbo/0
• Genetic Background: involves: 129S6/SvEvTac * C3H * C57BL/6

nervous system

amyloid beta deposits ( J:122372 )

• a significant increase in cortical the Abeta1-40 plaque number is seen in mice at 32 weeks of age compared transgenic mice on a wild-type background

• plaques are also increased in size

homeostasis/metabolism

amyloid beta deposits ( J:122372 )

• a significant increase in cortical the Abeta1-40 plaque number is seen in mice at 32 weeks of age compared transgenic mice on a wild-type background

• plaques are also increased in size

Genotype
MGI:4358884

cx5

• Allelic Composition: Nr1h2^tm1Djm/Nr1h2^tm1Djm; Nr1h3^tm1Djm/Nr1h3^tm1Djm
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:81696 )

• all mice die when given 10⁴ CFU of Listeria monocytogenes compared to all wild-type controls surviving

• at higher doses mice succumb to the infection 2-3 days earlier than controls

pregnancy-related premature death ( J:120923 )

• occasionally mothers fail to expulse pups from uterine horns leading rarely to death

reproductive system

abnormal spermatogonia proliferation ( J:120913 )

♂ • proliferation of male germ cells is significantly decreased compared to controls

abnormal female reproductive system morphology ( J:120923 )

♀

abnormal myometrium morphology ( J:120923 )

♀ • vacuoles filled with cholesterol esters are present within the myoctes

♀ • concentration of cholesterol esters are 32-fold higher at 3 months of age and 66-fold higher at 12 months of age

abnormal male reproductive system morphology ( J:120923 )

♂

abnormal seminiferous tubule morphology ( J:120913 )

♂ • 20-30% of 5.5 month old males have abnormal tubules with cellular aggregates clumping in the middle without any spermatozoa

♂ • by 10 months of age, most tubules are empty without any spermatozoa

abnormal Sertoli cell morphology ( J:120913 )

♂ • Sertoli cells have vacuoles filled with cholesterol esters within in them

seminiferous tubule degeneration ( J:120913 )

♂ • by 12 months of age, seminiferous tubules are degraded from deposits cholesterol

Leydig cell hypertrophy ( J:120913 )

♂ • Leydig cells in mice 3.5 months of age are enlarged

decreased testis weight ( J:120913 )

♂ • a significant decline in testis weight is noted starting at 9 weeks of age

testicular atrophy ( J:120913 )

♂ • as mice age, testis lose weight and morphology of the glands becomes becomes disrupted by cholesterol deposits

abnormal female reproductive system physiology ( J:120923 )

♀

abnormal parturition ( J:120923 )

♀ • occasionally mothers fail to expulse pups from uterine horns leading to hind-limb paralysis and rarely to death

abnormal uterus physiology ( J:120923 )

♀ • myometrium muscle has lower amplitudes of contraction compared to controls in response to pharmacological levels of oxytocin

abnormal male reproductive system physiology ( J:120923 )

♂

increased male germ cell apoptosis ( J:120913 )

♂ • apoptosis of germ cells within seminiferous tubules is more than double that of controls

♂ • ratio of proliferating/apoptotic male germ cells is significantly decreased compared to controls

reduced male fertility ( J:120913 )

♂ • male mice start exhibiting fertility problems around 5 months of age with complete loss of fertility occurring by 7 months of age

♂ • the fertility problems exhibited at 5 months of age include only 55% of mated females exhibiting vaginal plugs and dramatic reductions in litter size

homeostasis/metabolism

decreased circulating testosterone level ( J:120913 )

• testosterone production in the testes is significantly reduced compared to controls

decreased circulating luteinizing hormone level ( J:120913 )

• plasma LH levels are almost half that of controls

behavior/neurological

hindlimb paralysis ( J:120923 )

• occasionally mothers fail to expulse pups from uterine horns leading to hind-limb paralysis and rarely to death

immune system

abnormal macrophage morphology ( J:125452 )

• peritoneal macrophages have a 2.7-fold increase in free cholesterol and a 2.4-fold increase in total cholesterol

increased susceptibility to bacterial infection ( J:81696 )

• all mice die when given 10⁴ CFU of Listeria monocytogenes compared to all wild-type controls surviving

• at higher doses mice succumb to the infection 2-3 days earlier than controls

muscle

impaired smooth muscle contractility ( J:120923 )

• myometrium (uterus) muscle has lower amplitudes of contraction compared to controls in response to pharmacological levels of oxytocin

hematopoietic system

abnormal macrophage morphology ( J:125452 )

• peritoneal macrophages have a 2.7-fold increase in free cholesterol and a 2.4-fold increase in total cholesterol

abnormal bone marrow cell physiology ( J:125452 )

• when bone marrow is transferred into irradiated Apoe-null mice, bone marrow cells fail to lower total serum cholesterol levels as wild-type bone marrow cells do

• aortas from these mice have 3- to 8-fold more atherosclerotic lesions than Apoe-null mice receiving wild-type bone marrow

• increased atherosclerotic lesions are also observed when mutant bone marrow is transferred into LDLR-null mice

• spleens of recipient LDLR-null mice are also enlarged

endocrine/exocrine glands

abnormal seminiferous tubule morphology ( J:120913 )

♂ • 20-30% of 5.5 month old males have abnormal tubules with cellular aggregates clumping in the middle without any spermatozoa

♂ • by 10 months of age, most tubules are empty without any spermatozoa

abnormal Sertoli cell morphology ( J:120913 )

♂ • Sertoli cells have vacuoles filled with cholesterol esters within in them

seminiferous tubule degeneration ( J:120913 )

♂ • by 12 months of age, seminiferous tubules are degraded from deposits cholesterol

Leydig cell hypertrophy ( J:120913 )

♂ • Leydig cells in mice 3.5 months of age are enlarged

decreased testis weight ( J:120913 )

♂ • a significant decline in testis weight is noted starting at 9 weeks of age

testicular atrophy ( J:120913 )

♂ • as mice age, testis lose weight and morphology of the glands becomes becomes disrupted by cholesterol deposits

cellular

increased male germ cell apoptosis ( J:120913 )

♂ • apoptosis of germ cells within seminiferous tubules is more than double that of controls

♂ • ratio of proliferating/apoptotic male germ cells is significantly decreased compared to controls

abnormal spermatogonia proliferation ( J:120913 )

♂ • proliferation of male germ cells is significantly decreased compared to controls