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, all 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 c 14c°s. 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 c 14c°s 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.

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

“…Because accumulation of homogentisate caused no abnormalities in the livers and kidneys of patients with alkaptonuria (28), who lacked homogentisate oxidase activity, oxidative product(s) of homogentisic acid are the primary candidates causing various abnormalities seen in c 14CoS mice. This is consistent with observations on c 14CoS mice that express FAH following transgenic manipulations: the c 14CoS mouse was rescued by transgenic expression of FAH (10). The FAH-deficient mice treated with NTBC, an inhibitor of HPD, survived but developed hepatocellular carcinomas (16).…”

“…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.…”

“…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).…”

Functional annotation of mammalian genomic DNA sequence by chemical mutagenesis: A fine-structure genetic mutation map of a 1- to 2-cM segment of mouse chromosome 7 corresponding to human chromosome 11p14-p15

“…A few examples from our own ENU mutagenesis work on mouse Chr 7, plus the experiences of many other groups, illustrate this point. For example, we recently reported (28) two new point-mutation alleles of the fumarylacetoacetate hydrolase (Fah) gene, with one mimicking the neonatal lethality of the acute form of human tyrosinemia, type 1 [much like deletion or knockout alleles (29,30)]; and another, less-severe mutation mimicking the more chronic form of tyrosinemia in which pups live for several weeks before succumbing to the downstream effects of Fah insufficiency rather than its total absence. Likewise, ENU-induced allelic series with differing severities of effect at, for example, the eed (31-33), fit1 (34), Myo5a (35,36), and Bmp5 (3) genes provide unique reagents with which to explore gene structure-function relationships.…”

Morphogenetic competence of HNF4α-deficient mouse hepatic cells

“…In addition, deficient mouse liver shows profound ultrastructural abnormalities of the ER and Golgi [25]. FAH transcript levels were significantly depressed at all times (Fig.…”