Cited by 312Metabolism and Genetic DisordersAmino Acid Enzymes and MetabolismGlycogen Storage Diseases and Myoclonus

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

Grompe, Markus, Lindstedt, Sven, Al-Dhalimy, Muhsen, Kennaway, Nancy G., Papaconstantinou, John, Torres-Ramos, Carlos A., Ou, Ching-Nau, Finegold, Milton·1995·Nature Genetics

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.

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Crossref · 10.1038/ng0895-453

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Authors
Grompe, M., Lindstedt, S., Al-Dhalimy, M., Kennaway, N. G., Papaconstantinou, J., Torres-Ramos, C. A., Ou, C.-N., & Finegold, M.
Affiliations
  • Oregon Health & Science University (US)
  • Sahlgrenska University Hospital (SE)
  • The University of Texas Medical Branch at Galveston (US)
  • Texas Children's Hospital (US)
Venue
Nature Genetics
Published
1995-08
Volume
10
Issue
4
Pages
453-460
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
OpenAlex
W2073223227
Cited by
312
References
50
Citations by year
2026: 5 · 2025: 6 · 2024: 4 · 2023: 7 · 2022: 13 · 2021: 10 · 2020: 16 · 2019: 9 · 2018: 10 · 2017: 17 · 2016: 11 · 2015: 16 · 2014: 11 · 2013: 11 · 2012: 16
FWCI
5.26
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK048252, DK48252-02)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
Keywords
fumarylacetoacetate hydrolase, neonatal lethality, liver dysfunction, pharmacotherapy, hepatocellular carcinoma, hepatic gene expression, disease models
MeSH terms
alpha-Fetoproteins, Amino Acid Metabolism, Inborn Errors, Amino Acids, Animals, Cyclohexanones, Disease Models, Animal, Enzyme Inhibitors, Female, Heptanoates, Humans, Hydrolases, Liver, Liver Diseases, Liver Neoplasms, Male, Mice, Inbred C57BL, Nitrobenzoates, Pancreas, RNA, Messenger, Tyrosine, Mice

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