Point mutations in the murine fumarylacetoacetate hydrolase gene: Animal models for the human genetic disorder hereditary tyrosinemia type 1

Hereditary tyrosinemia type 1 (HT1) is a severe autosomal recessive metabol ic disease associated with point mutations in the human fumarylacetoacetate hydrolase (FAH) gene that disrupt tyrosine catabolism. An acute form of HT 1 results in death during the first months of life because of hepatic failu re, whereas a chronic form leads to gradual development of liver disease of ten accompanied by renal dysfunction, childhood rickets, neurological crisi s, and hepatocellular carcinoma. Mice homozygous for certain chromosome 7 d eletions of the albino Tyr; c locus that also include Fah die perinatally a s a result of liver dysfunction and exhibit a complex syndrome characterize d by structural abnormalities and alterations in gene expression in the liv er and kidney. Here we report that two independent, postnatally lethal muta tions induced by N-ethyl-N-nitrosourea and mapped near Tyr are alleles of F ah. 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 t he resulting mRNA, and a severe reduction of Fah mRNA levels. increased lev els of the diagnostic metabolite succinylacetone in the urine of the Fah(62 87SB) and Fah(5961SB) mutants indicate that these mutations cause a decreas e in Fah enzymatic activity. Thus, the neonatal phenotype present in both m utants is due to a deficiency in Fah caused by a point mutation, and we pro pose Fah(5961SB) and Fah(6287SB) as mouse models for acute and chronic form s of human HT1, respectively.