Phenotypes associated with this allele

• Allele Symbol: Nr1h4^tm1Gonz
• Allele Name: targeted mutation 1, Frank Gonzalez
• Allele ID: MGI:2137330
• Summary: 5 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Nr1h4^tm1Gonz/Nr1h4^tm1Gonz	involves: 129	MGI:3700546
hm2	Nr1h4^tm1Gonz/Nr1h4^tm1Gonz	involves: 129X1/SvJ	MGI:3806160
hm3	Nr1h4^tm1Gonz/Nr1h4^tm1Gonz	involves: 129X1/SvJ * C57BL/6	MGI:5437134
hm4	Nr1h4^tm1Gonz/Nr1h4^tm1Gonz	involves: 129X1/SvJ * C57BL/6N	MGI:2175162
hm5	Nr1h4^tm1Gonz/Nr1h4^tm1Gonz	STOCK Nr1h4^tm1Gonz/J	MGI:3847957

Genotype
MGI:3700546

hm1

• Allelic Composition: Nr1h4^tm1Gonz/Nr1h4^tm1Gonz
• Genetic Background: involves: 129

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

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:118368 )

N • normal plasma levels of testosterone

Genotype
MGI:3806160

hm2

• Allelic Composition: Nr1h4^tm1Gonz/Nr1h4^tm1Gonz
• Genetic Background: involves: 129X1/SvJ

liver/biliary system

abnormal bile composition ( J:129978 )

• the increase in the bile acid pool consists of increases in cholate and its derivates including taurocholic acid and taurodeoxycholic acid while other bile acids are found at normal levels

homeostasis/metabolism

increased circulating cholesterol level ( J:129978 )

• total cholesterol levels in serum are about double that found in wild-type mice

increased circulating triglyceride level ( J:129978 )

• serum triglyceride levels are significantly higher than in control mice

increased bile salt level ( J:129978 )

• serum bile acids are greatly elevated in these mice

• total bile acid pool collected from liver, gallbladder and small intestine is almost 2.5-fold higher than in controls

• the increases in the bile acid pool consist of increases in cholate and its derivates including taurocholic acid and taurodeoxycholic acid

Genotype
MGI:5437134

hm3

• Allelic Composition: Nr1h4^tm1Gonz/Nr1h4^tm1Gonz
• Genetic Background: involves: 129X1/SvJ * C57BL/6

liver/biliary system

increased hepatocyte apoptosis ( J:118204 )

• TUNEL staining indicates increased hepatocyte apoptosis as mutants age

liver inflammation ( J:118204 )

abnormal liver morphology ( J:118204 )

• starting at 9 months of age, some mutants display preneoplasms in the liver, with small foci becoming obvious at 12 months of age

• liver damage includes many vaculoles due to lipid deposits, vaculation due to cell damage, inflammation, and focal necrosis

• significant amounts of BrdU+ cells are detected around the damaged regions of the liver suggesting initiation of a compensatory regenerative proliferation

enlarged liver ( J:118204 )

• enlarged liver is not completely due to tumor formation because hepatomegaly is seen before tumors are observed

focal hepatic necrosis ( J:118204 )

increased liver tumor incidence ( J:118204 )

• both males and females develop liver tumors at 15 months of age of varying severity

• mutants fed a diet containing 2% cholestyramine, a bile acid-sequestering resin, for 3 months starting at 11 months of age when they do not have tumors, have a significantly reduced number and size of liver malignant lesions when they are older

increased hepatocellular carcinoma incidence ( J:118204 )

• tumors are typical hepatocellular adenoma and carcinoma

increased liver adenoma incidence ( J:118204 )

• tumors are typical hepatocellular adenoma and carcinoma

neoplasm

increased liver tumor incidence ( J:118204 )

• both males and females develop liver tumors at 15 months of age of varying severity

• mutants fed a diet containing 2% cholestyramine, a bile acid-sequestering resin, for 3 months starting at 11 months of age when they do not have tumors, have a significantly reduced number and size of liver malignant lesions when they are older

increased hepatocellular carcinoma incidence ( J:118204 )

• tumors are typical hepatocellular adenoma and carcinoma

increased liver adenoma incidence ( J:118204 )

• tumors are typical hepatocellular adenoma and carcinoma

cellular

increased hepatocyte apoptosis ( J:118204 )

• TUNEL staining indicates increased hepatocyte apoptosis as mutants age

homeostasis/metabolism

increased circulating aspartate transaminase level ( J:118204 )

• levels of alanine aminotransferase (ALT) are much higher in aging mutants than in controls, indicating increased liver damage

increased bile salt level ( J:118204 )

• serum and liver bile acid levels are higher in aging mutants than in wild-type controls

immune system

liver inflammation ( J:118204 )

growth/size/body

enlarged liver ( J:118204 )

• enlarged liver is not completely due to tumor formation because hepatomegaly is seen before tumors are observed

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hepatocellular carcinoma		DOID:684	OMIM:114550	J:118204 , J:170790

Genotype
MGI:2175162

hm4

• Allelic Composition: Nr1h4^tm1Gonz/Nr1h4^tm1Gonz
• Genetic Background: involves: 129X1/SvJ * C57BL/6N

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:64792 )

• about 30% of mutants die by day 7 when placed on a 1% cholic acid diet

growth/size/body

decreased body weight ( J:121075 )

• body weight is about 20% less than in wild-type mice, regardless of age

cachexia ( J:64792 )

• mutants on a 1% cholic acid diet exhibit severe wasting

decreased susceptibility to weight gain ( J:64792 )

• mutants on a 1% cholic acid diet exhibit a progressive decrease in body weight that results in about 1/3 of the initial body weight by day 5 of the diet

enlarged liver ( J:121075 )

• liver size, as a percentage of body weight, is higher than in wild-type mice at 12 months of age

homeostasis/metabolism

increased circulating cholesterol level ( J:64792 )

• mutants on a regular diet or on a 1% cholesterol diet exhibit increased serum total cholesterol levels

increased circulating phospholipid level ( J:64792 )

• mutants on a regular diet or on a 1% cholesterol diet exhibit increased phospholipid levels

increased circulating triglyceride level ( J:64792 )

• mutants on a regular or a 1% cholesterol diet exhibit increased triglyceride levels

decreased body temperature ( J:64792 )

• mutants on a 1% cholic acid diet exhibit hypothermia

abnormal bile salt homeostasis ( J:64792 )

• mutants on a regular diet and 1% cholic acid diet have fecal bile acid excretion about 2-fold and 4-fold, respectively, lower than in wild-type

• mutants on a 1% cholic acid diet exhibit higher (7-fold) urinary bile acid excretion rates than wild-type on the same diet

abnormal bile salt level ( J:64792 )

• mutants on a regular diet exhibit an 8-fold increase in total serum bile acid concentration

• mutants on a 1% cholic acid diet exhibit an 23-fold increase in total serum bile acid concentration

• mutants on a regular or 1% cholic acid diet have lower bile acid pool (about by 2 fold) than wild-type

increased bile salt level ( J:121075 )

• 3-fold and 5.6-fold increase in serum bile acid levels in young and older mutants, respectively, compared to wild-type mice

• hepatic bile acid levels are 2x as high as in wild-type mice at 12 months of age

increased liver cholesterol level ( J:64792 )

• mutants on a 1% cholesterol diet show 1.4-fold greater hepatic cholesterol levels

increased liver triglyceride level ( J:64792 )

• mutants on a regular diet show 2.2-fold greater hepatic triglyceride levels

• mutants on a 1% cholesterol diet show 2.4-fold greater hepatic triglyceride levels

liver/biliary system

increased hepatocyte apoptosis ( J:121075 )

• mutants exhibit an increase in hepatocyte apoptosis as indicated by an increase in TUNEL staining; 3 month old mutants show a higher level of apoptosis than 12 month old mutants

increased hepatocyte proliferation ( J:121075 )

• BrdU labeling indicates increased hepatocyte proliferation at 3 months of age compared to wild-type mice; at 12 months of age, proliferation has decreased but is still significantly higher than in controls

abnormal liver morphology ( J:64792 )

• mutants on a 1% cholic acid diet exhibit liver lesions indicative of severe hepatotoxicity, with numerous vacuolated and necrotic cells

enlarged liver ( J:121075 )

• liver size, as a percentage of body weight, is higher than in wild-type mice at 12 months of age

increased liver cholesterol level ( J:64792 )

• mutants on a 1% cholesterol diet show 1.4-fold greater hepatic cholesterol levels

increased liver triglyceride level ( J:64792 )

• mutants on a regular diet show 2.2-fold greater hepatic triglyceride levels

• mutants on a 1% cholesterol diet show 2.4-fold greater hepatic triglyceride levels

hepatic steatosis ( J:64792 )

• mutants on a regular diet or a 1% cholesterol diet exhibit more lipid containing vacuoles in the liver than wild-type

increased liver tumor incidence ( J:121075 )

• 64% of mutants at 12 months of age display preneoplastic foci

• 38% total tumor incidence in 12 month old mutants; older mice were not analyzed for further tumor incidence

• both male and female mutants have liver lesions at 12 months of age; degenerative lesions consist of hypertrophic and eosinophilic hepatocytes accompanied by proliferating oval cells and lipid disposition

• 9% of mutants at 12 months of age develop mixed tumors consisting of hepatocellular carcinoma and hepatocholangiocellular carcinoma; mixed tumor involves a fibrous stroma and immune cell infiltrate, ductile formation and fibrosis

increased hepatocellular carcinoma incidence ( J:121075 )

• 6% of mutants at 12 months of age develop hepatocellular carcinoma

increased liver adenoma incidence ( J:121075 )

• 36% of mutants at 12 months of age develop hepatocellular adenomas

cellular

increased hepatocyte apoptosis ( J:121075 )

• mutants exhibit an increase in hepatocyte apoptosis as indicated by an increase in TUNEL staining; 3 month old mutants show a higher level of apoptosis than 12 month old mutants

increased hepatocyte proliferation ( J:121075 )

• BrdU labeling indicates increased hepatocyte proliferation at 3 months of age compared to wild-type mice; at 12 months of age, proliferation has decreased but is still significantly higher than in controls

neoplasm

increased liver tumor incidence ( J:121075 )

• 64% of mutants at 12 months of age display preneoplastic foci

• 38% total tumor incidence in 12 month old mutants; older mice were not analyzed for further tumor incidence

• both male and female mutants have liver lesions at 12 months of age; degenerative lesions consist of hypertrophic and eosinophilic hepatocytes accompanied by proliferating oval cells and lipid disposition

• 9% of mutants at 12 months of age develop mixed tumors consisting of hepatocellular carcinoma and hepatocholangiocellular carcinoma; mixed tumor involves a fibrous stroma and immune cell infiltrate, ductile formation and fibrosis

increased hepatocellular carcinoma incidence ( J:121075 )

• 6% of mutants at 12 months of age develop hepatocellular carcinoma

increased liver adenoma incidence ( J:121075 )

• 36% of mutants at 12 months of age develop hepatocellular adenomas

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hepatocellular carcinoma		DOID:684	OMIM:114550	J:121075 , J:170790

Genotype
MGI:3847957

hm5

• Allelic Composition: Nr1h4^tm1Gonz/Nr1h4^tm1Gonz
• Genetic Background: STOCK Nr1h4^tm1Gonz/J

homeostasis/metabolism

increased circulating cholesterol level ( J:149005 )

increased circulating triglyceride level ( J:149005 )

increased circulating alanine transaminase level ( J:149005 )

increased circulating aspartate transaminase level ( J:149005 )