title: Multiple effects on liver-specific gene expression in albino lethal mice caused by deficiency of an enzyme in tyrosine metabolism.
abstract: alf/hsdr-1 is a locus in the mouse defined by albino deletions to be essential for neonatal viability. Homozygous deletion of alf/hsdr-1 leads to a pleiotropic phenotype in liver and kidney, including impaired perinatal activation of hormone-dependent genes, and the induction of detoxifying enzymes and early-response genes. To elucidate the molecular basis of this complex phenotype, we have identified the gene mapping at alf/hsdr-1 by positional cloning, using overlapping albino locus deletions to define the location of alf/hsdr-1. The gene encodes fumarylacetoacetate hydrolase, FAH, an enzyme of tyrosine metabolism. Genetically determined FAH deficiency in man leads to a severe liver failure in infants. In mice, we find that the normal sites of expression of FAH correlate tightly with cell-types which display abnormalities in albino lethal mice. The identification of the Fah gene as a candidate for alf/hsdr-1 offers a novel explanation for the complex phenotype, one into which all aspects can be accommodated. The phenotype can now be understood as a sequence of responses to toxic electrophilic metabolites.
authors.affiliation: Institute of Cell and Tumor Biology, German Cancer Research Center, Heidelberg.
authors.forename: G
authors.initials: G
authors.lastname: Kelsey
authors.forename: S
authors.initials: S
authors.lastname: Ruppert
authors.forename: A
authors.initials: A
authors.lastname: Schedl
authors.forename: E
authors.initials: E
authors.lastname: Schmid
authors.forename: E
authors.initials: E
authors.lastname: Thies
authors.forename: G
authors.initials: G
authors.lastname: Schütz
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D005804:Genes, Lethal; D006867:Hydrolases / Q000172:deficiency* / Q000235:genetics; D008099:Liver / Q000378:metabolism; D017093:Liver Failure / Q000235:genetics; D051379:Mice; D010641:Phenotype; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D014443:Tyrosine; D006867:Hydrolases; C020156:fumarylacetoacetase