Phenotypes Associated with This Genotype

Genotype
MGI:5558898

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

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

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