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Gene Review

Fah  -  fumarylacetoacetate hydrolase

Mus musculus

Synonyms: Beta-diketonase, FAA, Fumarylacetoacetase, Fumarylacetoacetate hydrolase
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Disease relevance of Fah


High impact information on Fah


Chemical compound and disease context of Fah

  • Hereditary tyrosinemia type 1 (HT1) (McKusick 276700), a severe autosomal recessive disorder of tyrosine metabolism, is caused by mutations in the fumarylacetoacetate hydrolase gene Fah (EC, which encodes the last enzyme in the tyrosine catabolic pathway [1].
  • We report here that fahA, the gene encoding Fah in the fungus Aspergillus nidulans, encodes a polypeptide showing 47.1% identity to its human homologue, fahA disruption results in secretion of succinylacetone (a diagnostic compound for human type I tyrosinaemia) and phenylalanine toxicity [8].
  • Analysis of a class of these mutations demonstrates that loss of homogentisate dioxygenase (leading to alkaptonuria in humans) prevents the effects of a Fah deficiency [8].
  • In an attempt to exploit the tumor hypoxia produced by FAA, we have combined it with the novel bioreductive drug SR 4233, a benzotriazine dioxide with high selective toxicity for hypoxic cells [9].
  • It was not recommended for phase II trial because of drug associated hypotension and the fact that it appeared to act as a pro-drug for flavone acetic acid (NSC 347512, LM 975, FAA) which was shown to be responsible for the dramatic solid tumor activity in mice [10].

Biological context of Fah

  • It is suggested that apoptotic death of renal tubular cells, as induced by administration of homogentisate to Fah-/- Hpd-/- mice, was caused by an intrinsic process, and that renal apoptosis and tubular dysfunctions in tubular cells occurred through different pathways [1].
  • The double mutant Fah -/- Hpd -/- mice grew normally without evidence of liver and renal disease, showing a phenotype similar to Hpd -/- mice [11].
  • To test this hypothesis, we have created lines of mice carrying Fah transgenes [12].
  • We find that c14CoS homozygotes which express transgenic Fah are complemented for all aspects of the complex lethal albino phenotype [12].
  • Mice homozygous for certain chromosome 7 deletions of the albino Tyr; c locus that also include Fah die perinatally as a result of liver dysfunction and exhibit a complex syndrome characterized by structural abnormalities and alterations in gene expression in the liver and kidney [4].

Anatomical context of Fah


Associations of Fah with chemical compounds


Enzymatic interactions of Fah


Other interactions of Fah


Analytical, diagnostic and therapeutic context of Fah


  1. A mouse model of renal tubular injury of tyrosinemia type 1: development of de Toni Fanconi syndrome and apoptosis of renal tubular cells in Fah/Hpd double mutant mice. Sun, M.S., Hattori, S., Kubo, S., Awata, H., Matsuda, I., Endo, F. J. Am. Soc. Nephrol. (2000) [Pubmed]
  2. Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice. Grompe, M., al-Dhalimy, M., Finegold, M., Ou, C.N., Burlingame, T., Kennaway, N.G., Soriano, P. Genes Dev. (1993) [Pubmed]
  3. Hepatocyte injury in tyrosinemia type 1 is induced by fumarylacetoacetate and is inhibited by caspase inhibitors. Kubo, S., Sun, M., Miyahara, M., Umeyama, K., Urakami, K., Yamamoto, T., Jakobs, C., Matsuda, I., Endo, F. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  4. Point mutations in the murine fumarylacetoacetate hydrolase gene: Animal models for the human genetic disorder hereditary tyrosinemia type 1. Aponte, J.L., Sega, G.A., Hauser, L.J., Dhar, M.S., Withrow, C.M., Carpenter, D.A., Rinchik, E.M., Culiat, C.T., Johnson, D.K. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  5. Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I. Overturf, K., Al-Dhalimy, M., Tanguay, R., Brantly, M., Ou, C.N., Finegold, M., Grompe, M. Nat. Genet. (1996) [Pubmed]
  6. Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I. Grompe, M., Lindstedt, S., al-Dhalimy, M., Kennaway, N.G., Papaconstantinou, J., Torres-Ramos, C.A., Ou, C.N., Finegold, M. Nat. Genet. (1995) [Pubmed]
  7. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Willenbring, H., Bailey, A.S., Foster, M., Akkari, Y., Dorrell, C., Olson, S., Finegold, M., Fleming, W.H., Grompe, M. Nat. Med. (2004) [Pubmed]
  8. Fungal metabolic model for human type I hereditary tyrosinaemia. Fernández-Cañón, J.M., Peñalva, M.A. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  9. Enhancement of the antitumor effect of flavone acetic acid by the bioreductive cytotoxic drug SR 4233 in a murine carcinoma. Sun, J.R., Brown, J.M. Cancer Res. (1989) [Pubmed]
  10. Flavone acetic acid--from laboratory to clinic and back. Bibby, M.C., Double, J.A. Anticancer Drugs (1993) [Pubmed]
  11. Tyrosinaemia type I and apoptosis of hepatocytes and renal tubular cells. Endo, F., Sun, M.S. J. Inherit. Metab. Dis. (2002) [Pubmed]
  12. Rescue of mice homozygous for lethal albino deletions: implications for an animal model for the human liver disease tyrosinemia type 1. Kelsey, G., Ruppert, S., Beermann, F., Grund, C., Tanguay, R.M., Schütz, G. Genes Dev. (1993) [Pubmed]
  13. Complete rescue of lethal albino c14CoS mice by null mutation of 4-hydroxyphenylpyruvate dioxygenase and induction of apoptosis of hepatocytes in these mice by in vivo retrieval of the tyrosine catabolic pathway. Endo, F., Kubo, S., Awata, H., Kiwaki, K., Katoh, H., Kanegae, Y., Saito, I., Miyazaki, J., Yamamoto, T., Jakobs, C., Hattori, S., Matsuda, I. J. Biol. Chem. (1997) [Pubmed]
  14. Sustained phosphorylation of Bid is a marker for resistance to Fas-induced apoptosis during chronic liver diseases. Vogel, A., Aslan, J.E., Willenbring, H., Klein, C., Finegold, M., Mount, H., Thomas, G., Grompe, M. Gastroenterology (2006) [Pubmed]
  15. N-ethyl-N-nitrosourea mutagenesis of a 6- to 11-cM subregion of the Fah-Hbb interval of mouse chromosome 7: Completed testing of 4557 gametes and deletion mapping and complementation analysis of 31 mutations. Rinchik, E.M., Carpenter, D.A. Genetics (1999) [Pubmed]
  16. The origin and liver repopulating capacity of murine oval cells. Wang, X., Foster, M., Al-Dhalimy, M., Lagasse, E., Finegold, M., Grompe, M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  17. Chronic liver disease in murine hereditary tyrosinemia type 1 induces resistance to cell death. Vogel, A., van Den Berg, I.E., Al-Dhalimy, M., Groopman, J., Ou, C.N., Ryabinina, O., Iordanov, M.S., Finegold, M., Grompe, M. Hepatology (2004) [Pubmed]
  18. Mechanistic inferences from the crystal structure of fumarylacetoacetate hydrolase with a bound phosphorus-based inhibitor. Bateman, R.L., Bhanumoorthy, P., Witte, J.F., McClard, R.W., Grompe, M., Timm, D.E. J. Biol. Chem. (2001) [Pubmed]
  19. Renal proximal tubular cells acquire resistance to cell death stimuli in mice with hereditary tyrosinemia type 1. Luijerink, M.C., van Beurden, E.A., Malingré, H.E., Jacobs, S.M., Grompe, M., Klomp, L.W., Berger, R., van den Berg, I.E. Kidney Int. (2004) [Pubmed]
  20. Interaction between the Ah receptor and proteins binding to the AP-1-like electrophile response element (EpRE) during murine phase II [Ah] battery gene expression. Vasiliou, V., Puga, A., Chang, C.Y., Tabor, M.W., Nebert, D.W. Biochem. Pharmacol. (1995) [Pubmed]
  21. In vivo correction of murine hereditary tyrosinemia type I by phiC31 integrase-mediated gene delivery. Held, P.K., Olivares, E.C., Aguilar, C.P., Finegold, M., Calos, M.P., Grompe, M. Mol. Ther. (2005) [Pubmed]
  22. Deficiency of an enzyme of tyrosine metabolism underlies altered gene expression in newborn liver of lethal albino mice. Ruppert, S., Kelsey, G., Schedl, A., Schmid, E., Thies, E., Schütz, G. Genes Dev. (1992) [Pubmed]
  23. Adenovirus-mediated gene therapy in a mouse model of hereditary tyrosinemia type I. Overturf, K., al-Dhalimy, M., Ou, C.N., Finegold, M., Tanguay, R., Lieber, A., Kay, M., Grompe, M. Hum. Gene Ther. (1997) [Pubmed]
  24. In vivo selection of hepatocytes transduced with adeno-associated viral vectors. Chen, S.J., Tazelaar, J., Moscioni, A.D., Wilson, J.M. Mol. Ther. (2000) [Pubmed]
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