Phenotypes associated with this allele

• Allele Symbol: Fah^tm1Mgo
• Allele Name: targeted mutation 1, Markus Grompe
• Allele ID: MGI:2429529
• Summary: 8 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Fah^tm1Mgo/Fah^tm1Mgo	either: (involves: 129S7/SvEvBrd) or (involves: 129S7/SvEvBrd * C57BL/6J)	MGI:2663890
hm2	Fah^tm1Mgo/Fah^tm1Mgo	involves: 129S7/SvEvBrd	MGI:4420951
hm3	Fah^tm1Mgo/Fah^tm1Mgo	involves: 129S7/SvEvBrd * C57BL	MGI:5558898
hm4	Fah^tm1Mgo/Fah^tm1Mgo	involves: 129S7/SvEvBrd * C57BL/6	MGI:4420928
hm5	Fah^tm1Mgo/Fah^tm1Mgo	involves: 129S7/SvEvBrd * PT	MGI:3617447
cx6	Cdkn1a^tm1Tyj/Cdkn1a^tm1Tyj Fah^tm1Mgo/Fah^tm1Mgo	involves: 129S2/SvPas * 129S7/SvEvBrd * C57BL/6	MGI:4420927
cx7	Fah^tm1Mgo/Fah^tm1Mgo Hgd^aku/Hgd^+	involves: 129S7/SvEvBrd * NB	MGI:3617441
cx8	Fah^tm1Mgo/Fah^tm1Mgo Hgd^aku/Hgd^aku	involves: 129S7/SvEvBrd * NB	MGI:3617440

Genotype
MGI:2663890

hm1

• Allelic Composition: Fah^tm1Mgo/Fah^tm1Mgo
• Genetic Background: either: (involves: 129S7/SvEvBrd) or (involves: 129S7/SvEvBrd * C57BL/6J)

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

mortality/aging

neonatal lethality, complete penetrance ( J:16046 )

• all alive at birth, but none survived past 24h after birth

homeostasis/metabolism

increased circulating creatinine level ( J:16046 )

• kidney dysfunction, as evidenced by elevated plasma levels of creatinine

hypoglycemia ( J:16046 )

• developed hypoglycemia during first few hours after birth

abnormal circulating aspartate transaminase level ( J:16046 )

• increased plasma levels of liver enzyme, aspartate amino transaminase (AST), indicative of hepatocellular damage

Genotype
MGI:4420951

hm2

• Allelic Composition: Fah^tm1Mgo/Fah^tm1Mgo
• Genetic Background: involves: 129S7/SvEvBrd

mortality/aging

increased susceptibility to xenobiotic induced morbidity/mortality ( J:105440 )

• following injection of homogentisic acid (HGA), 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC)-treated mice die within 70 hours unlike similarly treated mice off NTBC or after 2 weeks of ethanol feeding

• NTBC-treated mice die rapidly following administration of a high dose of the FAS agonist Jo-2 or challenged with acetaminophen unlike similarly treated mice off NTBC

liver/biliary system

decreased hepatocyte apoptosis ( J:105440 )

• following injection of HGA, mice off NTBC exhibit reduced hepatocyte apoptosis compared with similarly treated NTBC-treated mice

• mice off NTBC or on NTBC and treated with ethanol exhibit less apoptosis induced by Fas or APAP compared with NTBC-treated mice

liver failure ( J:105440 )

• following injection of HGA in NTBC-treated mice

homeostasis/metabolism

increased susceptibility to xenobiotic induced morbidity/mortality ( J:105440 )

• following injection of homogentisic acid (HGA), 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC)-treated mice die within 70 hours unlike similarly treated mice off NTBC or after 2 weeks of ethanol feeding

• NTBC-treated mice die rapidly following administration of a high dose of the FAS agonist Jo-2 or challenged with acetaminophen unlike similarly treated mice off NTBC

cellular

decreased hepatocyte apoptosis ( J:105440 )

• following injection of HGA, mice off NTBC exhibit reduced hepatocyte apoptosis compared with similarly treated NTBC-treated mice

• mice off NTBC or on NTBC and treated with ethanol exhibit less apoptosis induced by Fas or APAP compared with NTBC-treated mice

Genotype
MGI:5558898

hm3

• Allelic Composition: Fah^tm1Mgo/Fah^tm1Mgo
• Genetic Background: involves: 129S7/SvEvBrd * C57BL

cellular

abnormal hepatocyte mitochondrial morphology ( J:27735 )

mortality/aging

neonatal lethality, complete penetrance ( J:27735 )

• all pups die within 24 h of birth

• treatment with 2-(2-nitro-4-trifluoro-methylbenzyol)-I,3cyclohexanedione (NTBC) starting at E15 allows pups to survive past birth

liver/biliary system

liver/biliary system phenotype ( J:27735 )

N • liver function is normal in mice treated with NTBC

liver inflammation ( J:27735 )

• diffuse necroinflammatory lesions are seen by 5 weeks after cessation of NTBC treatment

abnormal liver lobule morphology ( J:27735 )

• lobular disarray is seen 10 weeks of age after stopping NTBC treatment

abnormal hepatocyte morphology ( J:27735 )

• marked nuclear pleomorphism and cell size variation are seen 13 weeks of age after stopping NTBC treatment

• after stopping treatment mice display dysplastic hepatocytes show nuclear pleomorphism with enlarged nucleoli and intranuclear lipid, cytoplasmic disorganization, focally enlarged mitochondria with paracrystalline arrays, elongated and tortuous cristae or loss of cristae and multiple clusters of aggregated intermediated filaments in the cytoplasm

abnormal hepatocyte mitochondrial morphology ( J:27735 )

increased liver tumor incidence ( J:27735 )

• focal nodular hyperplasia at 6 months of age in mice on NTBC treatment

• 3 of 6 mice treated continuously with NTBC had liver tumors (hepatocellular carcinoma or hepatoma) at 10 months of age

increased hepatocellular carcinoma incidence ( J:27735 )

• at 7 months of age in 3 mice

• often are multiple, expansile nodules with relatively well differentiated trabecular or cord-like growth patterns

increased hepatoma incidence ( J:27735 )

increased liver adenoma incidence ( J:27735 )

• in 1 mouse a well-demarcated adenoma of lipid filled hepatocytes was detected

abnormal hepatocyte physiology ( J:27735 )

• contain enormous quantities of alpha-fetoprotein

homeostasis/metabolism

abnormal amino acid level ( J:27735 )

abnormal circulating amino acid level ( J:27735 )

• generalized increase in all amino acid levels after stopping NTBC treatment

• both NTBC treated and untreated mice accumulate succinylacteone

increased circulating tyrosine level ( J:27735 )

• hypertyrosinemia; tyrosine levels are elevated both before and after stopping NTBC

aminoaciduria ( J:27735 )

• in 4 of 5 mice after stopping NTBC treatment

increased circulating bilirubin level ( J:27735 )

• elevated conjugated bilirubin levels within 2 weeks of stopping NTBC treatment

increased circulating aspartate transaminase level ( J:27735 )

• elevated AST levels within 2 weeks of stopping NTBC treatment

increased alpha-fetoprotein level ( J:27735 )

• hepatocytes contain enormous quantities of alpha-fetoprotein after stopping NTBC treatment

neoplasm

increased liver tumor incidence ( J:27735 )

• focal nodular hyperplasia at 6 months of age in mice on NTBC treatment

• 3 of 6 mice treated continuously with NTBC had liver tumors (hepatocellular carcinoma or hepatoma) at 10 months of age

increased hepatocellular carcinoma incidence ( J:27735 )

• at 7 months of age in 3 mice

• often are multiple, expansile nodules with relatively well differentiated trabecular or cord-like growth patterns

increased hepatoma incidence ( J:27735 )

increased liver adenoma incidence ( J:27735 )

• in 1 mouse a well-demarcated adenoma of lipid filled hepatocytes was detected

renal/urinary system

enlarged kidney ( J:27735 )

aminoaciduria ( J:27735 )

• in 4 of 5 mice after stopping NTBC treatment

kidney degeneration ( J:27735 )

• focal degeneration and regeneration of the proximal tubular epithelium and aggregates of cytoplasmic microfilaments in 3 of 7 mice after stopping NTBC treatment

pale kidney ( J:27735 )

endocrine/exocrine glands

increased pancreatic alpha cell number ( J:27735 )

• in 3 of 5 mice off NTBC treatment

pancreas hyperplasia ( J:27735 )

• hyperplasia of the islets in 3 of 5 mice off NTBC treatment

immune system

liver inflammation ( J:27735 )

• diffuse necroinflammatory lesions are seen by 5 weeks after cessation of NTBC treatment

growth/size/body

pancreas hyperplasia ( J:27735 )

• hyperplasia of the islets in 3 of 5 mice off NTBC treatment

enlarged kidney ( J:27735 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
tyrosinemia type I		DOID:0050726	OMIM:276700	J:27735

Genotype
MGI:4420928

hm4

• Allelic Composition: Fah^tm1Mgo/Fah^tm1Mgo
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:138701 )

• mice die within 4 days of partial hepatectomy and NTBC withdrawal unlike similarly treated wild-type mice

liver/biliary system

abnormal hepatocyte morphology ( J:138701 )

• following NTBC withdrawal, hepactocytes are dysplastic with increased DNA damage compared with cells from similarly treated wild-type mice

increased hepatocellular carcinoma incidence ( J:138701 )

• within 1 year after treatment with 5% of the normal NTBC dose

abnormal liver physiology ( J:138701 )

• following NTBC withdrawal, hepatocytes exhibit increased DNA damage compared with similarly treated wild-type cells

decreased hepatocyte proliferation ( J:138701 )

• 40 hours after partial hepatectomy and NTBC withdrawal, no hepatocyte proliferation is detected unlike in similarly treated wild-type mice

abnormal liver regeneration ( J:138701 )

• following partial hepatectomy and NTBC withdrawal, hepatocytes exhibit decreased proliferation then die due to liver failure within 4 days compared to in similarly treated wild-type mice

impaired liver regeneration ( J:138701 )

• following partial hepatectomy and NTBC withdrawal, regeneration is blocked unlike in similarly treated wild-type mice

neoplasm

increased hepatocellular carcinoma incidence ( J:138701 )

• within 1 year after treatment with 5% of the normal NTBC dose

growth/size/body

weight loss ( J:138701 )

• following NTBC withdrawal

enlarged kidney ( J:138701 )

• mild following NTBC withdrawal

homeostasis/metabolism

aminoaciduria ( J:138701 )

• following NTBC withdrawal

increased susceptibility to injury ( J:138701 )

• following partial hepatectomy and NTBC withdrawal, hepatocytes exhibit no proliferation and mice die due to liver failure within 4 days compared to in similarly treated wild-type mice

renal/urinary system

enlarged kidney ( J:138701 )

• mild following NTBC withdrawal

aminoaciduria ( J:138701 )

• following NTBC withdrawal

cellular

decreased hepatocyte proliferation ( J:138701 )

• 40 hours after partial hepatectomy and NTBC withdrawal, no hepatocyte proliferation is detected unlike in similarly treated wild-type mice

Genotype
MGI:3617447

hm5

• Allelic Composition: Fah^tm1Mgo/Fah^tm1Mgo
• Genetic Background: involves: 129S7/SvEvBrd * PT

Liver disease in Fah^tm1Mgo/Fah^tm1Mgo mice and liver histology of Fah^tm1Mgo/Fah^tm1Mgo Hgd^aku/Hgd^aku and Fah^tm1Mgo/Fah^tm1Mgo Hgd^aku/Hgd⁺ mice after treatment with the drug NTCB

homeostasis/metabolism

increased circulating tyrosine level ( J:77295 )

• plasma tyrosine levels become elevated after withdrawal from 2-(2-N-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC)

liver/biliary system

pale liver ( J:77295 )

• after withdrawal from NTBC

abnormal liver physiology ( J:77295 )

• abnormal liver function

jaundice ( J:77295 )

• after withdrawal from NTBC

renal/urinary system

kidney inflammation ( J:77295 )

• after withdrawal from NTBC

dilated renal tubule ( J:77295 )

• after withdrawal from NTBC

growth/size/body

weight loss ( J:77295 )

• lose weight and become sick after withdrawal from NTBC

immune system

kidney inflammation ( J:77295 )

• after withdrawal from NTBC

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
tyrosinemia type I		DOID:0050726	OMIM:276700	J:77295

Genotype
MGI:4420927

cx6

• Allelic Composition: Cdkn1a^tm1Tyj/Cdkn1a^tm1Tyj; Fah^tm1Mgo/Fah^tm1Mgo
• Genetic Background: involves: 129S2/SvPas * 129S7/SvEvBrd * C57BL/6

mortality/aging

mortality/aging ( J:138701 )

N • mice survive NTBC withdrawal unlike similarly treated Fah^tm1Mgo homozygotes

neoplasm

increased hepatocellular carcinoma incidence ( J:138701 )

• 7 to 8 weeks following NTBC withdrawal and 8 weeks following low-dose NTBC treatment, mice develop hepatocellular carcinomas unlike similarly treated Fah^tm1Mgo homozygotes

• tumors that develop following treatment with low-dose NTBC are smaller and fewer than those in mice following complete withdrawal of NTBC

increased renal carcinoma incidence ( J:138701 )

• in 80% of mice 12 weeks after NTBC withdrawal

liver/biliary system

abnormal hepatocyte morphology ( J:138701 )

• following NTBC withdrawal, hepactocytes are dysplastic with increased DNA damage compared with cells from similarly treated Fah^tm1Mgo homozygotes

increased hepatocellular carcinoma incidence ( J:138701 )

• 7 to 8 weeks following NTBC withdrawal and 8 weeks following low-dose NTBC treatment, mice develop hepatocellular carcinomas unlike similarly treated Fah^tm1Mgo homozygotes

• tumors that develop following treatment with low-dose NTBC are smaller and fewer than those in mice following complete withdrawal of NTBC

abnormal liver physiology ( J:138701 )

• following NTBC withdrawal, hepatocytes exhibit increased DNA damage compared with similarly treated cells from Fah^tm1Mgo homozygotes

increased hepatocyte apoptosis ( J:138701 )

• following NTBC withdrawal

increased hepatocyte proliferation ( J:138701 )

• following NTBC withdrawal unlike in similarly treated Fah^tm1Mgo homozygotes

renal/urinary system

kidney cyst ( J:138701 )

• 10 weeks after NTBC withdrawal, mice develop macroscopic cysts comprised of renal parenchyma unlike similarly treated Fah^tm1Mgo homozygotes

increased renal carcinoma incidence ( J:138701 )

• in 80% of mice 12 weeks after NTBC withdrawal

dilated proximal convoluted tubule ( J:138701 )

• following NTBC withdrawal

growth/size/body

weight loss ( J:138701 )

• following NTBC withdrawal, mice exhibit weight loss with a plateau at 5 and 6 weeks after withdrawal compared with similarly treated Fah^tm1Mgo homozygotes

kidney cyst ( J:138701 )

• 10 weeks after NTBC withdrawal, mice develop macroscopic cysts comprised of renal parenchyma unlike similarly treated Fah^tm1Mgo homozygotes

cellular

increased hepatocyte apoptosis ( J:138701 )

• following NTBC withdrawal

increased hepatocyte proliferation ( J:138701 )

• following NTBC withdrawal unlike in similarly treated Fah^tm1Mgo homozygotes

Genotype
MGI:3617441

cx7

• Allelic Composition: Fah^tm1Mgo/Fah^tm1Mgo; Hgd^aku/Hgd⁺
• Genetic Background: involves: 129S7/SvEvBrd * NB

Liver disease in Fah^tm1Mgo/Fah^tm1Mgo mice and liver histology of Fah^tm1Mgo/Fah^tm1Mgo Hgd^aku/Hgd^aku and Fah^tm1Mgo/Fah^tm1Mgo Hgd^aku/Hgd⁺ mice after treatment with the drug NTCB

homeostasis/metabolism

increased circulating tyrosine level ( J:77295 )

• plasma tyrosine levels become elevated after withdrawl from NTBC

liver/biliary system

abnormal liver morphology ( J:77295 )

• after withdrawl from NTBC

abnormal hepatocyte morphology ( J:77295 )

• nodules of normal hepatocytes among abnormal hepatocytes

pale liver ( J:77295 )

abnormal liver physiology ( J:77295 )

• abnormal liver function after withdrawl from NTBC

jaundice ( J:77295 )

• after withdrawl from NTBC

renal/urinary system

kidney inflammation ( J:77295 )

• after withdrawl from NTBC

dilated renal tubule ( J:77295 )

• after withdrawl from NTBC

growth/size/body

weight loss ( J:77295 )

• loose weight and become sick after withdrawl from NTBC

immune system

kidney inflammation ( J:77295 )

• after withdrawl from NTBC

Genotype
MGI:3617440

cx8

• Allelic Composition: Fah^tm1Mgo/Fah^tm1Mgo; Hgd^aku/Hgd^aku
• Genetic Background: involves: 129S7/SvEvBrd * NB

Liver disease in Fah^tm1Mgo/Fah^tm1Mgo mice and liver histology of Fah^tm1Mgo/Fah^tm1Mgo Hgd^aku/Hgd^aku and Fah^tm1Mgo/Fah^tm1Mgo Hgd^aku/Hgd⁺ mice after treatment with the drug NTCB

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:77295 )

N • mice remain healthy even when the drug NTCB is withdrawn

N • plasma tyrosine levels are normal

liver/biliary system

liver/biliary system phenotype ( J:77295 )

N • normal liver function and histology

renal/urinary system

renal/urinary system phenotype ( J:77295 )

N • kidneys normal