Point mutations in the Murine Fah gene : animal models for the human genetic disorder hereditary tyrosinemia type 1

Hereditary tyrosinemia type 1 (HT1) is a severe autosomal recessive metabolic disease, associated with point mutations in the human fumarylacetoacetate hydrolase (FAH) gene that cause disruption of tyrosine catabolism. The acute form results in death during the first months of life due to hepatic failure, while the chronic form leads to gradual liver disease development often accompanied by renal dysfunction, childhood rickets, neurological crisis, and hepatocellular carcinoma. In the mouse, Fah maps near the albino (c) locus in chromosome 7. Mice homozygous for specific deletions around c that include Fah die perinatally as a result of liver dysfunction and exhibit a complex syndrome characterized by structural abnormalities of the liver and kidney, and alterations in gene expression. Here we report that two mutations induced by N-ethyl-N-nitrosourea (ENU) and mapped near c are alleles of Fah. The fah^6287SB allele is a missense mutation in exon 6 causing a reduction of Fah mRNA levels, 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. The identification of mutations was determined by DNA sequencing, and Fah expression analysis was carried out by northern blot analysis. Increased levels of the diagnostic metabolite succinylacetone in the urine of the fah^6287SB and fah^5961SB mutants, identified by gas chromatography / mass spectrometry, indicates that the 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 the acute and chronic forms of HT1, respectively.