Human Genetics

, Volume 93, Issue 6, pp 615–619 | Cite as

Two missense mutations causing tyrosinemia type 1 with presence and absence of immunoreactive fumarylacetoacetase

  • Helge Rootwelt
  • Janice Chou
  • William A. Gahl
  • Ruud Berger
  • Turgay Coşkun
  • Else Brodtkorb
  • Eli Anne Kvittingen
Original Investigations


Hereditary tyrosinemia type 1, due to a deficiency of fumarylacetoacetase (FAH), is characterized by progressive liver damage and renal tubular dysfunction and may occur in an acute or a chronic form. An Ala 134 to Asp (GCT to GAT) transition was found in one Turkish and two Norwegian patients with chronic tyrosinemia. SphI digestion of polymerase chain reaction (PCR) amplified genomic DNA identified the mutation and showed that the patients were heterozygous. All these patients had immunoreactive FAH protein in fibroblasts. Another Norwegian patient with chronic disease, without FAH immunoreactive material in fibroblasts, had a Pro 342 to Leu mutation (CCG to CTG). This mutation was identified by MspI digestion of PCR amplified genomic DNA, and the patient was heterozygous. Northern blotting showed FAH mRNA of normal size and amounts in all patients. Site directed mutagenesis and translation in a rabbit reticulocyte lysate demonstrated that both mutations abolished FAH activity.


Polymerase Chain Reaction Northern Blotting Missense Mutation Liver Damage Chronic Form 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Agsteribbe E, Faassen H van, Hartog MV, Reversma T, Taanman JW, Pannekoek H, Evers RF, Welling GM, Berger R (1990) Nucleotide sequence of cDNA encoding human fumarylacetoacetase. Nucleic Acids Res 18:1887.Google Scholar
  2. Ansorge W, Sproat B, Stegeman J, Schwager C, Zenke M (1987) Automatic DNA sequencing: ultrasensitive detection of fluorescent bands during electrophoresis. Nucleic Acids Res 15:4593–4602.Google Scholar
  3. Balnaves ME, Nasioulas S, Dahl HHM, Forrest S (1991) Direct PCR from CVS and blood lysates for detection of cystic fibrosis and Duchenne muscular dystrophy deletions. Nucleic Acids Res 19:1155.Google Scholar
  4. Bednarczuk TA, Wiggins RC, Konat GW (1991) Generation of high efficiency, single-stranded DNA hybridisation probes by PCR. BioTechniques 10:478.Google Scholar
  5. Berger R, Faassen H van, Taanman JW, Vries H de, Agsteribbe E (1987) Type I tyrosinemia: lack of immunologically detectable fumarylacetoacetase enzyme protein in tissues and cell extracts. Pediatr Res 22:394–398.Google Scholar
  6. Berger R, Faassen H van, Taanman JW, Vries H de, Agsteribbe E (1988) Different types of mutations in the chronic and acute forms of type I tyrosinemia. Pediatr Res 24:266 (abstract).Google Scholar
  7. Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol chloroform extraction. Anal Biochem 162:156–159.CrossRefPubMedGoogle Scholar
  8. Cleveland DW, Lopata MA, MacDonald RJ, Cowan NJ, Rutter WJ, Kirschner MW (1980) Number and evolutionary conservation of α- and β-tubulin and cytoplasmic β- and γ-actin genes using specific cloned cDNA probes. Cell 20:95–105.Google Scholar
  9. Coşkun T, Özalp I, Koçak N, Yüce A, Çaglar M, Berger R (1991) Type 1 tyrosinemia: Presentation of 11 cases. J Inherited Metab Dis 14:765–770.Google Scholar
  10. Goldsmith LA, Laberge C (1989) Tyrosinemia and related disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 547–562.Google Scholar
  11. Grompe M, Al-Dhalimy (1992) Nucleotide sequence of a cDNA encoding murine fumarylacetoacetate hydrolase. Biochem Med Metab Biol 48:26–31.Google Scholar
  12. Hultman T, Stahl S, Homes E, Uhlén M (1989) Direct solid phase sequencing of genomic and plasmid DNA using magnetic beads as solid support. Nucleic Acids Res 17:4937–4946.Google Scholar
  13. Hultman T, Bergh S, Moks T, Uhlén M (1991) Bidirectional solid-phase sequencing of in vitro-amplified plasmid DNA. BioTechniques 10:84–93.Google Scholar
  14. Kristensen T, Voss H, Schwage C, Stegeman J, Sproat B, Ansorge W (1988) T7 polymerase in automated dideoxy sequencing. Nucleic Acids Res 16:3487–3496.Google Scholar
  15. Kvittingen EA, Brodtkorb E (1986) The pre- and post-natal diagnosis of tyrosinemia type I and the detection of carrier state by assay of fumarylacetoacetase. Scand J Clin Lab Invest 46 [Suppl 184]:35–40.Google Scholar
  16. Kvittingen EA, Jellum E, Stokke O, Fiatmark A, Bergan A, Sødal G, Halvorsen S, Schrumpf E, Gjone E (1986) Liver transplantation in a 23-year-old tyrosinemia patient: effects of the renal tubular dysfunction. J Inherited Metab Dis 9:216–224.Google Scholar
  17. Kvittingen EA, Talseth T, Halvorsen S, Jacobs C, Hovig T, Flatmark A (1991) Renal failure in adult patients with hereditary tyrosinemia type I. J Inherited Metab Dis 14:53–62.Google Scholar
  18. Kvittingen EA, Rootwelt H, Dam T van, Faassen H van, Berger R (1992) Hereditary tyrosinemia type I: lack of correlation between clinical findings and amount of immunoreactive fumary lacetoacetase protein. Pediatr Res 31:43–46.Google Scholar
  19. Kvittingen EA, Rootwelt H, Brandzæg P, Bergan A, Berger R (1993) Hereditary tyrosinemia type I; self induced correction of the fumarylacetoacetase defect. J Clin Invest 91:1816–1821.Google Scholar
  20. Labelle Y, Phaneuf D, Tanguay RM (1991) Cloning and expression analysis of a cDNA encoding fumarylacetoacetate hydrolase: post-transcriptional modulation in rat liver and kidney. Gene 104:197–202.Google Scholar
  21. Lindstedt S, Holme E, Lock EA, Hjalmarson O, Strandvik B (1992) Treatment of hereditary tyrosinemia type 1 by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet 340:813–817.Google Scholar
  22. Phaneuf D, Labelle Y, Bérubé D, Arden K, Cavenee W, Gagné R, Tanguay RM (1991) Cloning and expression of the cDNA encoding human fumarylacetoacetate hydrolase, the enzyme deficient in hereditary tyrosinemia: Assignment of the gene to chromosome 15. Am J Hum Genet 48:525–535.Google Scholar
  23. Phaneuf D, Lambert M, Laframboise R, Mitchell G, Lettre F, Tanguay RM (1992) Type 1 hereditary tyrosinemia: Evidence for molecular heterogeneity and identification of a causal mutation in a French Canadian patient. J Clin Invest 90:1185–1192.Google Scholar
  24. Rootwelt H, Kvittingen EA, Agsteribbe E, Hartog MV, Faassen H van, Berger R (1992) The human fumarylacetoacetase gene: characterization of restriction fragment length polymorphisms and identification of haplotypes in tyrosinemia type I and pseudodeficiency. Hum Genet 89:229–233.Google Scholar
  25. Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA (1988) Primer-directed enzymatic amplification of cDNA with a thermostable DNA polymerase. Science 239:487–491.PubMedGoogle Scholar
  26. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning — a laboratory manual, 2nd edn. Cold Spring Harbor Laboratory Press, Cold Spring Habor, NY, pp 7.43–7.45.Google Scholar
  27. Tanguay RM, Valet JP, Lescault A, Duband JL, Laberge C, Lettre F, Plante M (1990) Different molecular basis for fumarylacetoacetate hydrolase deficiency in the two clinical forms of hereditary tyrosinemia (type I). Am J Hum Genet 47:308–316.Google Scholar
  28. Weinberg AG, Mize CE, Worthen HG (1976) The occurrence of hepatoma in the chronic form of hereditary tyrosinemia. J Pediatr 88:434–438.Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Helge Rootwelt
    • 1
  • Janice Chou
    • 2
  • William A. Gahl
    • 2
  • Ruud Berger
    • 3
  • Turgay Coşkun
    • 4
  • Else Brodtkorb
    • 1
  • Eli Anne Kvittingen
  1. 1.Institute of Clinical BiochemistryUniversity of OsloRikshospitaletNorway
  2. 2.National Institute of Child Health and Human DevelopmentBethesdaUSA
  3. 3.Wilhelmina KinderziekenhuisUtrechtThe Netherlands
  4. 4.Institute of Child HealthHacettepe UniversityAnkaraTurkey

Personalised recommendations