FAH

Abstract

Fumarylacetoacetate hydrolase (FAH) catalyzes the last step in tyrosine degradation, the conversion of fumarylacetoacetate to fumarate and acetoacetate. FAH deficiency is the cause of hereditary tyrosinemia type 1, a severe autosomal recessive metabolic disease caused by an error in tyrosine degradation. Most children die within one year after birth of liver failure, renal tubular dysfunction, and cardiomyopathy. This chapter presents a study in which FAH–/– mice were not embryonic lethal, but died within 24 hours of birth from generalized liver dysfunction. Hepatic mRNAs inducible by cAMP were decreased and mRNAs inducible by DNA or oxidative damage were elevated. The phenotype could be rescued by administration of NTBC (2-(2-nitro-4-trifluoro methylbenzoyl)-l, 3-cyclohexanedione) to pregnant heterozygotes. NTBC inhibited 4-OH phenylpyruvate dioxygenase, an enzyme upstream of FAH in tyrosine degradation. NTBC treated homozygotes were completely normal and could breed. Discontinuation of NTBC in adulthood gave rise to a phenotype analogous to human tyrosinemia type 1: progressive liver failure, renal tubular dysfunction, pancreatic islet hyperplasia, and hepatocarcinoma. Histologically, mutants showed hepatocellular dysplasia and necroinflammation in the liver