Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Genetics volume 10, pages 453–460 (1995)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Mitchell, G.A., Lambert, M. & Tanguay, P.M. in The metabolic and molecular basis of inherited disease, (eds Scriver, C.R., Beaudet, A.L, Sly, W. & Valte, D.) 1077–1106 (MacGraw-Hill, New York, 1994).

    Google Scholar 

  2. Russo, P. & O'Regan, S. Visceral pathology of hereditary tyrosinemia type I. Am. J. hum. Genet. 47, 317–324 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Mitchell, G. et al Neurologic crises in hereditary tyrosinemia. New Engl. J. Med. 322, 432–437 (1990).

    Article  CAS  Google Scholar 

  4. Perry, T.L. Tyrosinemia associated with hypermethioninemia and islet cell hyperplasia. Can. Med. Ass. J. 97, 1067–1075 (1967).

    CAS  PubMed  Google Scholar 

  5. Edwards, M.A., Green, A., Colli, A. & Rylance, G. Tyrosinaemia type I and hypertrophic obstructive cardiomyopathy. Lancet. 1, 1437–1438 (1987).

    Article  CAS  Google Scholar 

  6. Kvittingen, E. Hereditary tyrosinemia type I-an overview. Scand. J. din. Lab. Invest. 46, 27–34 (1986).

    Article  CAS  Google Scholar 

  7. Grompe, M. et al. Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice. Genes Dev. 7, 2298–2307 (1993).

    Article  CAS  Google Scholar 

  8. Gluecksohn-Waelsch, S., Schiffman, M.B., Thorndike, J. & Cori, C.F. Complementation studies of lethal alleles in the mouse causing deficiencies of glucose-6-phosphatase, tyrosine aminotransferase, and serine dehydratase. Proc. natn. Acad. Sci. U.S.A. 71, 825–629 (1974).

    Article  CAS  Google Scholar 

  9. Gluecksohn-Waelsch, S. Genetic control of morphogenetic and biochemical differentiation: lethal albino deletions in the mouse. Cell 16, 225–237 (1979).

    Article  CAS  Google Scholar 

  10. Giometti, C.S. et al. Evidence for regulatory genes on mouse chromosome 7 that affect the quantitative expression of proteins in the fetal and newborn liver. Proc. natn. Acad. Sci. U.S.A. 89, 2448–2452 (1992).

    Article  CAS  Google Scholar 

  11. Ruppert, S. et al. Two genetically defined transacting loci coordinately regulate overlapping sets of liver-specific genes. Cell. 61, 895–904 (1990).

    Article  CAS  Google Scholar 

  12. McKnight, S.L., Lane, M.D. & Gluecksohn-Waelsch, S. CCAAT/enhancer-binding protein a central regulator of energy metabolism? Genes Dev. 3, 2021–2024 (1989).

    Article  CAS  Google Scholar 

  13. Kelsey, G. et al Rescue of mice homozygous for lethal albino deletions: implications for an animal model for the human liver disease tyrosinemia type 1. Genes Dev. 7, 2285–2297 (1993).

    Article  CAS  Google Scholar 

  14. Klebig, M.L., Rusell, L.B. & Rinchik, E.M. Murine fumarylacetoacetate hydrolase (Fah) gene is disrupted by a neonatally lethal albino deletion that defines the hepatocyte-specific developmental regulation 1 (hsdr-1)locus. Proc. natn. Acad. Sci. U.S.A. 89, 1363–1367 (1992).

    Article  CAS  Google Scholar 

  15. Ruppert, S. et al. Deficiency of an enzyme of tyrosine metabolism underlies altered gene expression in newborn liver of lethal albino mice. Genes Dev. 6, 1430–1443 (1992).

    Article  CAS  Google Scholar 

  16. Lindstedt, S., Holme, E., Lock, E.A., Hjalmarson, O. & Strandvik, B. Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet 340, 813–817 (1992).

    Article  CAS  Google Scholar 

  17. Tönjes, R.R., Xanthopoulos, K.G., Darnell, J.E.J. & Paul, D. Transcriptional control in hepatocytes of normal and c14CoS albino deletion mice. EMBO J. 11, 127–133 (1992).

    Article  Google Scholar 

  18. Loose, D.S. et al. Trans regulation of the phosphoenolpyruvate carboxykinase (GTP) gene, identified by deletions in chromosome 7 of the mouse. Proc. natn. Acad. Sci. U.S.A. 83, 5184–5188 (1986).

    Article  CAS  Google Scholar 

  19. Sala-Trepat, J.M. et al. A lethal deletion on mouse chromosome 7 affects regulation of liver cell-specific functions: Posttranscriptional control of serum protein and transcriptional control of aldolase B synthesis. Proc. natn. Acad. Sci. U.S.A. 82, 2442–2446 (1985).

    Article  CAS  Google Scholar 

  20. DeFranco, D., Morris, S.M., Jr Leonard, C.M. & Gluecksohn-Waelsch, S. Metallothionein mRNA expression in mice homozygous for chromosomal deletions around the albino locus. Proc. natn. Acad. Sci. U.S.A. 85, 1161–1164 (1988).

    Article  CAS  Google Scholar 

  21. Zaret, K.S., Milos, P., Lia, M., Bali, D. & Gluecksohn, W.S. Selective loss of a DNase I hypersensitive site upstream of the tyrosine aminotransferase gene in mice homozygous for lethal albino deletions. Proc. natn. Acad. Sci. U.S.A. 89, 6540–6544 (1992).

    Article  CAS  Google Scholar 

  22. Vacher, J., Camper, S.A., Krumlauf, R., Compton, R.S. & Tilghman, S.M. raf regulates the postnatal repression of the mouse alpha-fetoprotein gene at the posttranscriptional level. Molec. cell. Biol. 12, 856–864 (1992).

    Article  CAS  Google Scholar 

  23. Bisgaard, H.C., Nagy, P., Ton, P.T., Hu, Z. & Thorgeirsson, S.S. Modulation of keratin 14 and alpha-fetoprotein expression during hepatic oval cell proliferation and liver regeneration. J. cell Physiol. 159, 475–484 (1994).

    Article  CAS  Google Scholar 

  24. Pitkanen, S. et al. Serum levels of oncofetal markers CA 125, CA 19-9, and alpha-fetoprotein in children with hereditary tyrosinemia type I. Pediat. Res. 35, 205–208 (1994).

    Article  CAS  Google Scholar 

  25. Piantino, P., Arrigoni, A., Brunette, M.R. & Gindro, T. Alpha-fetoprotein in hepatic pathology and hepatocarcinoma. J. Nucl. Med. Allied Sci. 33, 34–38 (1989).

    CAS  PubMed  Google Scholar 

  26. Wyss, P.A., Boynton, S.B., Chu, J., Spencer, R.F. & Roth, K.S. Physiological basis for an animal model of the renal Fanconi syndrome: use of succinylacetone in the rat. Clin. Sci. 83, 81–87 (1992).

    Article  CAS  Google Scholar 

  27. Grenier, A. & Lescault, A. in Methods of enzymatic analysis, (ed. Bergmeyer, H.-U.) 73–79 (VCH Verlagsgesellschaft, Weinheim, F.R. Germany, 1985).

    Google Scholar 

  28. Smith, I. in Chromatography and electrophoretic techniques, (ed. Smith, I.) 104–121 (John Wiley & Sons, New York, 1969).

    Google Scholar 

  29. Blanchard, H. et al. Pediatric liver transplantation: the Montreal experience. J. Pediat. Surg. 24, 1009–1012 (1989).

    Article  CAS  Google Scholar 

  30. Kalayoglu, M. et al. Liver transplantation in infants and children. J. Pediat. Surg. 24, 70–76 (1989).

    Article  CAS  Google Scholar 

  31. Reznik, G.K. & Pad berg, G. Diethylnitrosamine-induced metastasizing hepatocellular carcinomas in New Zealand white rabbits. A tumor model for clinical investigations. J. Cancer Res. Clin. Oncol. 117, 123–129 (1991).

    Article  CAS  Google Scholar 

  32. Mauad, T.H. et al. Mice with homozygous disruption of the mdr2 P-glycoprotein gene. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis. Am. J. Pathol. 145, 1237–1245 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Ullrich, S.J., Zeng, Z.Z. & Jay, G. Transgenic mouse models of human gastric and hepatic carcinomas. Semin. Cancer Biol. 5, 61–68 (1994).

    CAS  PubMed  Google Scholar 

  34. Mori, M. et al. The LEC rat: a model for human hepatitis, liver cancer, and much more. Am. J. Pathol. 144, 200–204 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Gerin, J.L. Experimental WHV infection of woodchucks: an animal model of hepadnavirus-induced liver cancer. Gastroenterol. Jpn. 2, 38–42 (1990).

    Article  Google Scholar 

  36. Nebert, D.W., Puga, A. & Vasiliou, V. Role of the Ah receptor and the dioxin-inducible [Ah] gene battery in toxicity, cancer, and signal transduction. Ann. N.Y. Acad. Sci. 685, 624–640 (1993).

    Article  CAS  Google Scholar 

  37. Mullis, K.B. & Faloona, F.A. Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction. Meth. Enzym. 155, 335–350 (1987).

    CAS  Google Scholar 

  38. Miller, S.A., Dykes, D.D. & Polesky, H.F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucl. Acids Res. 16, 1215 (1988).

    Article  CAS  Google Scholar 

  39. Sturman, J.A. & Applegarth, D.A. in Neuromethods. (eds Boulton, A.A., Baker, G.B. & Wood, J.D.) (Humana Press Inc., Clifton, 1985).

    Google Scholar 

  40. Winston, S.E., Fuller, S.A. & Hurrell, J.G.R. in Current protocols in molecular biology, (ed. Ausubel, P.M.) 10.8.1–10.8.17 (Green Publishing Associates, Inc., New York, 1993).

    Google Scholar 

  41. Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 (1987).

    Article  CAS  Google Scholar 

  42. Sambrook, J., Fritsch, E.F. & Maniatis, T. in Molecular cloning: a laboratory manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1989).

    Google Scholar 

  43. Grompe, M. & AI-Dhalimy, M. Nucleotide sequence of a cDNA encoding murine fumarylacetoacetate hydrolase. Biochem. Med. Metab. Biol. 48, 26–31 (1992).

    Article  CAS  Google Scholar 

  44. Lem, J., Chin, A.C., Thayer, M.J., Leach, R.J. & Foumier, R.E. Coordinate regulation of two genes encoding gluconeogenic enzymes by the trans-dominant locusTse-1. Proc. natn. Acad. Sci. U.S.A. 85, 7302–7306 (1988).

    Article  CAS  Google Scholar 

  45. Surh, L.C., Beaudet, A.L. & O'Brien, W.E. Molecular characterization of the murine argininosuccinate synthetase locus. Gene. 99, 181–189 (1991).

    Article  CAS  Google Scholar 

  46. Veres, G., Gibbs, R.A., Scherer, S.E. & Caskey, C.T. The molecular basis of the sparse fur mouse mutation. Science 237, 415–417 (1987).

    Article  CAS  Google Scholar 

  47. Rabek, J.P., Hoyt, P.R., Zhang, D.E., Izban, M.G. & Papaconstantinou, J. Derepression of a mouse alpha-fetoprotein expression vector in COS-1 cells by amplification of specific cis-acting sequences of the AFP promoter. Nucl. Acids Res. 18, 6677–6682 (1990).

    Article  CAS  Google Scholar 

  48. Ron, D. & Habener, J.F. CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Genes Dev. 6, 439–453 (1992).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland, Oregon, 97201, USA

    Markus Grompe, Muhsen Al-Dhalimy & Nancy G. Kennaway

  2. Department of Pediatrics, Oregon Health Sciences University, Portland, Oregon, 97201, USA

    Markus Grompe

  3. Department of Clinical Chemistry, Sahlgren's Hospital, Gothenburg University, Gothenburg, S-41345, Sweden

    Sven Lindstedt

  4. Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas, 77555, USA

    John Papaconstantinou & Carlos A. Torres-Ramos

  5. Department of Pathology, Texas Children's Hospital, Houston, Texas, 77030, USA

    Ching-Nau Ou & Milton Finegold

Authors
  1. Markus Grompe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sven Lindstedt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Muhsen Al-Dhalimy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nancy G. Kennaway
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John Papaconstantinou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carlos A. Torres-Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ching-Nau Ou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Milton Finegold
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grompe, M., Lindstedt, S., Al-Dhalimy, M. et al. Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I. Nat Genet 10, 453–460 (1995). https://doi.org/10.1038/ng0895-453

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0895-453

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing