Deficiency of an enzyme of tyrosine metabolism underlies altered gene expression in newborn liver of lethal albino mice.

Abstract

Mice homozygous for albino deletions encompassing the locus alf/hsdr-1 die shortly after birth. Lethality is thought to be the consequence of hypoglycemia, which results from the failure to activate hormone-dependent genes in liver and kidney encoding enzymes important for gluconeogenesis. Within the region in which alf/hsdr.1 has been defined by physical mapping, we identified the gene encoding fumarylacetoacetate hydrolase (FAH), an enzyme of tyrosine metabolism. Lack of FAH activity should lead to accumulation of toxic tyrosine metabolites. In man, genetically determined FAH deficiency is the primary defect in tyrosinemia type I, a fatal liver disease of infants. Northern blot and in situ hybridization analysis of mouse tissues showed that the cell types that normally express FAH correspond to those that exhibit a phenotype in alf/hsdr-1 deletion mice. Moreover, we could mimic aspects of the alf/hsdr-1 deletion phenotype in vitro by treating primary hepatocyte cultures with an intermediate of tyrosine metabolism. These findings strongly suggest that alf/hsdr-1 encodes FAH and that absence of FAH is responsible for neonatal lethality in albino deletion mice. Mechanisms by which this metabolic defect might bring about alterations in gene expression characteristic of the alf/hsdr-1 deletion phenotype are discussed.

Complete Rescue of Lethal Albino c Mice by Null Mutation of 4-Hydroxyphenylpyruvate Dioxygenase and Induction of Apoptosis of Hepatocytes in These Mice by in VivoRetrieval of the Tyrosine Catabolic Pathway

“…Sudden apoptotic death of unmasked phenotype of HT1 in mature and unmodified hepatocytes had not been expected (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)16), and these are implications for the pathogenesis and treatment of liver disease in HT1 patients. We suggest that mature and unmodified hepatocytes in those with the FAH defect cannot survive and that hepatocytes in the chronic form of HT1 have to be protected from a likely acute death.…”

“…Mice with the genotype Fah ϩ/Ϫ Hpd Ϫ/Ϫ were identified and used for the next breeding for generation of Fah Ϫ/Ϫ Hpd Ϫ/Ϫ mice. Heterozygotes for the Fah Ϫ allele (Fah ϩ/Ϫ ) were identified by Southern blots using the RN.Fd probe (a gift from G. Schü tz) as described (8,9). Homozygotes for the Fah Ϫ allele (Fah Ϫ/Ϫ ) were identified by the absence of exon 2 sequences and the presence of exon 8 sequences of the Fah gene after PCR amplification of regions containing each exon, respectively.…”

“…Studies on these mice revealed impairment of expression of developmentally regulated genes that are essential for liver functions (6 -11). These abnormalities led to neonatal death probably due to hypoglycemia (8). The hepatocyte injuries seen in HT1 patients have not been evidenced in these mice, but ultrastructural investigations on these lethal albino mice revealed altered membranous components of hepatocytes in the perinatal period (9).…”

“…Lethal albino deletion c 14CoS mice and mice with targetdisrupted Fah are models for HT1 (5)(6)(7)(8)(9)(10)(11)(12), but these mice die in the perinatal period, bearing a phenotype different from that seen in HT1 patients (5)(6)(7)(8)(9). Studies on these mice revealed impairment of expression of developmentally regulated genes that are essential for liver functions (6 -11).…”

“…In this study, we asked if homozygous null mutation of the Hpd gene would rescue the homozygous c 14CoS mice (c14CoS/ c 14CoS or Fah Ϫ/Ϫ ) (5,8,9,12). HPD catalyzes a complex reaction to form homogentisate from 4-hydroxyphenylpyruvate.…”