title: Rescue of mice homozygous for lethal albino deletions: implications for an animal model for the human liver disease tyrosinemia type 1.
abstract: Mice homozygous for specific deletions around the albino locus on chromosome 7 die within the first few hours of birth. They have a complex phenotype in liver and kidney, which includes multiple changes in gene expression and ultrastructural abnormalities. On the basis of this phenotype, it was proposed that these deletions remove a regulatory locus, alf or hsdr-1. Recently, we and others showed that the gene for fumarylacetoacetate hydrolase (Fah), an enzyme involved in tyrosine catabolism, was disrupted by the lethal albino deletion c14CoS. The finding that the Fah gene in wild-type mice is highly expressed only in cell types that develop a phenotype in mutants, and the fact that Fah deficiency determines the human liver disease hereditary tyrosinemia type 1 (HT1), suggested that disruption of the Fah gene was responsible for the lethal albino phenotype. To test this hypothesis, we have created lines of mice carrying Fah transgenes. We find that c14CoS homozygotes which express transgenic Fah are complemented for all aspects of the complex lethal albino phenotype. Moreover, the degree to which the phenotype is corrected depends on the level of transgenic Fah expression. These results unequivocally establish Fah as the gene mapping at alf/hsdr-1 and prove that the phenotype depends ultimately on the blockage of tyrosine metabolism. Finally, they suggest lethal albino mice as an animal model for HT1.
authors.affiliation: Division Molecular Biology of the Cell I, 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: F
authors.initials: F
authors.lastname: Beermann
authors.forename: C
authors.initials: C
authors.lastname: Grund
authors.forename: R M
authors.initials: RM
authors.lastname: Tanguay
authors.forename: G
authors.initials: G
authors.lastname: Schütz
mesh_terms: D000417:Albinism / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D017353:Gene Deletion; D015870:Gene Expression / Q000502:physiology; D006720:Homozygote; D006801:Humans; D006867:Hydrolases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D007003:Hypoglycemia / Q000235:genetics; D008099:Liver / Q000648:ultrastructure; D008107:Liver Diseases / Q000097:blood / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D014443:Tyrosine / Q000097:blood*
chemical_list: D014443:Tyrosine; D006867:Hydrolases; C020156:fumarylacetoacetase