Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I

Markus Grompe, Sven Lindstedt, Muhsen Al-Dhalimy, Nancy G. Kennaway, John Papaconstantinou, Carlos A. Torres-Ramos, Ching Nau Ou, Milton Finegold

Research output: Contribution to journalArticlepeer-review

244 Scopus citations

Abstract

Hereditary tyrosinaemia type I, a severe autosomal recessive metabolic disease, affects the liver and kidneys and is caused by deficiency of fumarylacetoacetate hydrolase (FAH). Mice homozygous for a FAH gene disruption have a neonatal lethal phenotype caused by liver dysfunction and do not represent an adequate model of the human disease. Here we demonstrate that treatment of affected animals with 2–(2–nitro–4–trifluoro–methylbenzyol)–1,3–cyclohexanedione abolished neonatal lethality, corrected liver function and partially normalized the altered expression pattern of hepatic mRNAs. The prolonged lifespan of affected animals resulted in a phenotype analogous to human tyrosinaemia type I including hepatocellular carcinoma. The adult FAH−/− mouse will serve as useful model for studies of the pathophysiology and treatment of hereditary tyrosinaemia type I as well as hepatic cancer.

Original languageEnglish (US)
Pages (from-to)453-460
Number of pages8
JournalNature genetics
Volume10
Issue number4
DOIs
StatePublished - Aug 1995

ASJC Scopus subject areas

  • Genetics

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