title: Point mutations in the murine fumarylacetoacetate hydrolase gene: Animal models for the human genetic disorder hereditary tyrosinemia type 1.
abstract: Hereditary tyrosinemia type 1 (HT1) is a severe autosomal recessive metabolic disease associated with point mutations in the human fumarylacetoacetate hydrolase (FAH) gene that disrupt tyrosine catabolism. An acute form of HT1 results in death during the first months of life because of hepatic failure, whereas a chronic form leads to gradual development of liver disease often accompanied by renal dysfunction, childhood rickets, neurological crisis, and hepatocellular carcinoma. Mice homozygous for certain chromosome 7 deletions of the albino Tyr; c locus that also include Fah die perinatally as a result of liver dysfunction and exhibit a complex syndrome characterized by structural abnormalities and alterations in gene expression in the liver and kidney. Here we report that two independent, postnatally lethal mutations induced by N-ethyl-N-nitrosourea and mapped near Tyr are alleles of Fah. The Fah(6287SB) allele is a missense mutation in exon 6, and Fah(5961SB) is a splice mutation causing loss of exon 7, a subsequent frameshift in the resulting mRNA, and a severe reduction of Fah mRNA levels. Increased levels of the diagnostic metabolite succinylacetone in the urine of the Fah(6287SB) and Fah(5961SB) mutants indicate that these mutations cause a decrease in Fah enzymatic activity. Thus, the neonatal phenotype present in both mutants is due to a deficiency in Fah caused by a point mutation, and we propose Fah(5961SB) and Fah(6287SB) as mouse models for acute and chronic forms of human HT1, respectively.
authors.affiliation: Division of Biology, University of Tennessee, Knoxville, TN 37996-0910, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Aponte
authors.forename: G A
authors.initials: GA
authors.lastname: Sega
authors.forename: L J
authors.initials: LJ
authors.lastname: Hauser
authors.forename: M S
authors.initials: MS
authors.lastname: Dhar
authors.forename: C M
authors.initials: CM
authors.lastname: Withrow
authors.forename: D A
authors.initials: DA
authors.lastname: Carpenter
authors.forename: E M
authors.initials: EM
authors.lastname: Rinchik
authors.forename: C T
authors.initials: CT
authors.lastname: Culiat
authors.forename: D K
authors.initials: DK
authors.lastname: Johnson
mesh_terms: D000208:Acute Disease; D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D015415:Biomarkers; D002908:Chronic Disease; D003433:Crosses, Genetic; D018076:DNA, Complementary / Q000235:genetics; D004790:Enzyme Induction; D005038:Ethylnitrosourea; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D005796:Genes; D005804:Genes, Lethal; D006537:Heptanoates / Q000652:urine; D006801:Humans; D006867:Hydrolases / Q000172:deficiency / Q000235:genetics*; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D023421:Models, Animal; D008969:Molecular Sequence Data; D016296:Mutagenesis; D020125:Mutation, Missense; D017354:Point Mutation; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020176:Tyrosinemias / Q000201:enzymology / Q000235:genetics* / Q000652:urine
chemical_list: D015415:Biomarkers; D018076:DNA, Complementary; D006537:Heptanoates; D012333:RNA, Messenger; C020804:succinylacetone; D006867:Hydrolases; C020156:fumarylacetoacetase; D005038:Ethylnitrosourea