Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I
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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The Fah5981SB mouse is ideal to study gene repair because it is point-mutation-based and fully recapitulates the human disease on an accelerated time scale.
“The Fah5981SB mouse is ideal to study gene repair, because it is point-mutation– based and fully recapitulates the human disease on an accelerated time scale.”
From Adeno‐associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo†‡ (2010) · cites this paper as [27]
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Adenovirus-Mediated Gene Therapy in a Mouse Model of Hereditary Tyrosinemia Type I
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Ex Vivo Hepatic Gene Therapy of a Mouse Model of Hereditary Tyrosinemia Type I
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Self-citationIn Vivo Genetic Selection of Renal Proximal Tubules
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Self-citationFirst-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure
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Expansion, in vivo–ex vivo cycling, and genetic manipulation of primary human hepatocytes
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Self-citationDevelopment of Humanized Mouse models to Study Human Malaria Parasite Infection
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Principles of therapeutic liver repopulation
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Self-citationA facile method for somatic, lifelong manipulation of multiple genes in the mouse liver
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Generation of Healthy Mice from Gene-Corrected Disease-Specific Induced Pluripotent Stem Cells
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Liver repopulation for the treatment of metabolic diseases
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Self-citationEngraftment of Bone Marrow‐Derived Epithelial Cells
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In vivo suppressor mutations correct a murine model of hereditary tyrosinemia type I
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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
- Semantic Scholar
- 475d9ce000d032d0d790441f5db803f2c24584d3
- 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
- Licence
- www.springer.com/tdm (tdm)
- 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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