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.

Unified gas chromatographic?mass spectrometric method for quantitating tyrosine metabolites in urine and plasma

“…Mutations in FAH disrupt tyrosine catabolism (Fig. 1) and lead to the accumulation of fumarylacetoacetate (FAA), maleylacetoaetate (MAA), succinylacetoacetate (SAA), MA and FA in liver and kidney that are believed to be responsible for the hepato-renal manifestations of the disease [6]. The accumulated SAA is readily converted to SA which inhibits a proximal step in heme synthesis and leads to the build up of the putative nerotoxin ␦-aminolevulinate (␦-ALA).…”

Genome editing for the reproduction and remedy of human diseases in mice

“…Such a case was reported in a mouse model for the remedy for human hereditary tyrosinemia type I (HTI), which is a fatal recessive genetic disease caused by mutation of an essential gene in the tyrosine catabolic pathway, fumarylacetoacetate hydrolase (FAH) [25]. The mouse model for human HTI, called Fah5981SB mouse strain, carries a G>A point mutation at the boundary of exon 8 and intron 8 of Fah locus [26], which leads to aberrant splicing of mRNA. Fah deficiency causes accumulation of toxic metabolites in hepatocytes and leads to liver damage and body weight loss.…”

Disruption of Fumarylacetoacetate Hydrolase Causes Spontaneous Cell Death under Short-Day Conditions in Arabidopsis

“…Studies on human HT1 and its animal models have shown that the accumulation of MAA, FAA, succinylacetoacetate, and succinylacetone causes direct tissue damage (Lindblad et al, 1977;Grompe et al, 1993;Sun et al, 2000;Aponte et al, 2001;Jorquera and Tanguay, 2001;Bergeron et al, 2006). In this study, we found that treatment of Arabidopsis wild-type seedlings with succinylacetone is able to mimic the sscd1 cell death phenotype (Fig.…”

“…In both human HT1 and mouse fah mutants, the metabolic intermediates (MAA, FAA, succinylacetoacetate, and succinylacetone) were highly accumulated, which are toxic to cells and tissues (Lindblad et al, 1977;Grompe et al, 1993;Aponte et al, 2001;Jorquera and Tanguay, 2001). Due to technical difficulties, it is so far not possible to detect these metabolic intermediates in entire worms (Fisher et al, 2008) and in Arabidopsis plants (data not shown).…”