LOSS OF FUMARYLACETOACETATE HYDROLASE IS RESPONSIBLE FOR THE NEONATALHEPATIC-DYSFUNCTION PHENOTYPE OF LETHAL ALBINO MICE

Mice homozygous for the c14CoS albino deletion die as neonates as a re sult of liver dysfunction. Previous mapping studies have associated th is defect with a 310-kb fragment encoding the hepatocyte-specific deve lopmental regulation locus (alf/hsdr-1). The gene encoding fumarylacet oacetate hydrolase (Fah), a metabolic enzyme that catalyzes the last s tep of tyrosine catabolism, also maps to the same deletion interval. T o test whether the neonatal defects found in the albino deletion mutan ts are attributable to loss of Fah, and not to another gene mapping to the deletion, we have generated Fah mutant mice by gene targeting in embryonic stem cells. Fah-deficient mice die within 12 hr after birth from hypoglycemia and liver dysfunction. In addition, the same pattern of altered liver mRNA expression found in the albino deletion mutants was also found in affected animals . We conclude that the neonatal le thal and liver dysfunction phenotype of the alf/hsdr-1 deletion is ent irely attributable to loss of Fah.