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J Clin Invest. 1992 October; 90(4): 1185–1192.
PMCID: PMC443158

Type 1 hereditary tyrosinemia. Evidence for molecular heterogeneity and identification of a causal mutation in a French Canadian patient.


Type 1 hereditary tyrosinemia (HT1) is a metabolic disorder caused by a deficiency of fumarylacetoacetate hydrolase (FAH). Using a full-length FAH cDNA and specific antibodies, we investigated liver specimens from seven unrelated HT1 patients (six of French Canadian and one of Scandinavian origin). The expression of FAH in livers of these individuals was analyzed at several molecular levels including mRNA, immunoreactive material (IRM), and enzymatic activity. Four phenotypic variants were differentiated by these assays: (i) presence of FAH mRNA without any IRM or enzymatic activity, (ii) decreased FAH mRNA, IRM, and enzymatic activity, (iii) moderately decreased FAH mRNA and IRM with severely reduced enzymatic activity, and (iv) undetectable FAH mRNA, IRM, and enzymatic activity. These various molecular phenotypes suggest that this disorder may be caused by a variety of FAH mutations. Interestingly, we found no apparent relationship between the clinical and the molecular phenotypes, except that patients with absent IRM and enzymatic activity tend to have higher levels of serum alpha-fetoprotein and an earlier clinical onset. To further analyze the molecular basis of HT1, the FAH cDNA of a patient designated as variant A was amplified and sequenced. An A-to-T transversion, which substitutes asparagine16 with isoleucine (N16I), was identified. This patient was heterozygous as shown by direct sequencing of the amplified region and hybridization with allele-specific oligonucleotide probes. The N16I allele originates from the father and the second allele appears not to be expressed in the liver of the proband. CV-1 cells transfected with the mutant cDNA produced FAH mRNA, but no protein or hydrolytic activity, as predicted by the "A" phenotype of the patient. This is the first demonstration of heterogeneity in the expression of FAH at the levels of protein, mRNA, and enzymatic activity in the livers of HT1 patients and is the first identification of a causal mutationin this disease.

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  • Lindblad B, Lindstedt S, Steen G. On the enzymic defects in hereditary tyrosinemia. Proc Natl Acad Sci U S A. 1977 Oct;74(10):4641–4645. [PubMed]
  • Stoner E, Starkman H, Wellner D, Wellner VP, Sassa S, Rifkind AB, Grenier A, Steinherz PG, Meister A, New MI, et al. Biochemical studies of a patient with hereditary hepatorenal tyrosinemia: evidence of glutathione deficiency. Pediatr Res. 1984 Dec;18(12):1332–1336. [PubMed]
  • Gagné R, Lescault A, Grenier A, Laberge C, Mélançon SB, Dallaire L. Prenatal diagnosis of hereditary tyrosinaemia: measurement of succinylacetone in amniotic fluid. Prenat Diagn. 1982 Jul;2(3):185–188. [PubMed]
  • De Braekeleer M, Larochelle J. Genetic epidemiology of hereditary tyrosinemia in Quebec and in Saguenay-Lac-St-Jean. Am J Hum Genet. 1990 Aug;47(2):302–307. [PubMed]
  • Kvittingen EA. Hereditary tyrosinemia type I--an overview. Scand J Clin Lab Invest Suppl. 1986;184:27–34. [PubMed]
  • Russo P, O'Regan S. Visceral pathology of hereditary tyrosinemia type I. Am J Hum Genet. 1990 Aug;47(2):317–324. [PubMed]
  • Mitchell G, Larochelle J, Lambert M, Michaud J, Grenier A, Ogier H, Gauthier M, Lacroix J, Vanasse M, Larbrisseau A, et al. Neurologic crises in hereditary tyrosinemia. N Engl J Med. 1990 Feb 15;322(7):432–437. [PubMed]
  • Tanguay RM, Valet JP, Lescault A, Duband JL, Laberge C, Lettre F, Plante M. Different molecular basis for fumarylacetoacetate hydrolase deficiency in the two clinical forms of hereditary tyrosinemia (type I). Am J Hum Genet. 1990 Aug;47(2):308–316. [PubMed]
  • Berger R, Van Faassen H, Taanman JW, De Vries H, Agsteribbe E. Type I tyrosinemia: lack of immunologically detectable fumarylacetoacetase enzyme protein in tissues and cell extracts. Pediatr Res. 1987 Oct;22(4):394–398. [PubMed]
  • Nicole LM, Valet JP, Laberge C, Tanguay RM. Purification of mRNA coding for the enzyme deficient in hereditary tyrosinemia, fumarylacetoacetate hydrolase. Biochem Cell Biol. 1986 May;64(5):489–493. [PubMed]
  • Phaneuf D, Labelle Y, Bérubé D, Arden K, Cavenee W, Gagné R, Tanguay RM. 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. 1991 Mar;48(3):525–535. [PubMed]
  • Labelle Y, Phaneuf D, Tanguay RM. Cloning and expression analysis of a cDNA encoding fumarylacetoacetate hydrolase: post-transcriptional modulation in rat liver and kidney. Gene. 1991 Aug 15;104(2):197–202. [PubMed]
  • Demers SI, Phaneuf D, Tanguay RM. TaqI RFLP for the human fumarylacetoacetate hydrolase (FAH) gene. Nucleic Acids Res. 1991 Mar 25;19(6):1352–1352. [PMC free article] [PubMed]
  • Demers SI, Tanguay RM. Bg1II RFLP for the human fumarylacetoacetate hydrolase (FAH) gene. Nucleic Acids Res. 1991 Apr 25;19(8):1965–1965. [PMC free article] [PubMed]
  • Demers SI, Tanguay RM. KpnI and RsaI RFLPs for the human fumarylacetoacetate hydrolase (FAH) gene. Nucleic Acids Res. 1991 Apr 25;19(8):1965–1965. [PMC free article] [PubMed]
  • Demers SI, Tanguay RM. MspI RFLP in the human fumarylacetoacetate hydrolase (FAH) gene. Nucleic Acids Res. 1991 Dec 25;19(24):6971–6971. [PMC free article] [PubMed]
  • Turcotte B, Guertin M, Chevrette M, Bélanger L. Rat alpha 1-fetoprotein messenger RNA: 5'-end sequence and glucocorticoid-suppressed liver transcription in an improved nuclear run-off assay. Nucleic Acids Res. 1985 Apr 11;13(7):2387–2398. [PMC free article] [PubMed]
  • Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. [PubMed]
  • Khandjian EW. UV crosslinking of RNA to nylon membrane enhances hybridization signals. Mol Biol Rep. 1986;11(2):107–115. [PubMed]
  • Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. [PubMed]
  • Kvittingen EA, Talseth T, Halvorsen S, Jakobs C, Hovig T, Flatmark A. Renal failure in adult patients with hereditary tyrosinaemia type I. J Inherit Metab Dis. 1991;14(1):53–62. [PubMed]
  • Paradis K, Weber A, Seidman EG, Larochelle J, Garel L, Lenaerts C, Roy CC. Liver transplantation for hereditary tyrosinemia: the Quebec experience. Am J Hum Genet. 1990 Aug;47(2):338–342. [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PubMed]
  • Higuchi RG, Ochman H. Production of single-stranded DNA templates by exonuclease digestion following the polymerase chain reaction. Nucleic Acids Res. 1989 Jul 25;17(14):5865–5865. [PMC free article] [PubMed]
  • Bell GI, Karam JH, Rutter WJ. Polymorphic DNA region adjacent to the 5' end of the human insulin gene. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5759–5763. [PubMed]
  • Gorman CM, Moffat LF, Howard BH. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. [PMC free article] [PubMed]
  • Kvittingen EA, Rootwelt H, van Dam T, van Faassen H, Berger R. Hereditary tyrosinemia type I: lack of correlation between clinical findings and amount of immunoreactive fumarylacetoacetase protein. Pediatr Res. 1992 Jan;31(1):43–46. [PubMed]
  • Zhong N, Martiniuk F, Tzall S, Hirschhorn R. Identification of a missense mutation in one allele of a patient with Pompe disease, and use of endonuclease digestion of PCR-amplified RNA to demonstrate lack of mRNA expression from the second allele. Am J Hum Genet. 1991 Sep;49(3):635–645. [PubMed]
  • Klebig ML, Russell LB, Rinchik EM. 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 Natl Acad Sci U S A. 1992 Feb 15;89(4):1363–1367. [PubMed]
  • Chou PY, Fasman GD. Prediction of the secondary structure of proteins from their amino acid sequence. Adv Enzymol Relat Areas Mol Biol. 1978;47:45–148. [PubMed]
  • Walker DC, McCloskey DA, Simard LR, McInnes RR. Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9625–9629. [PubMed]
  • Wang T, Okano Y, Eisensmith RC, Harvey ML, Lo WH, Huang SZ, Zeng YT, Yuan LF, Furuyama JI, Oura T, et al. Founder effect of a prevalent phenylketonuria mutation in the Oriental population. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2146–2150. [PubMed]
  • Brody LC, Mitchell GA, Obie C, Michaud J, Steel G, Fontaine G, Robert MF, Sipila I, Kaiser-Kupfer M, Valle D. Ornithine delta-aminotransferase mutations in gyrate atrophy. Allelic heterogeneity and functional consequences. J Biol Chem. 1992 Feb 15;267(5):3302–3307. [PubMed]
  • Laberge C. Hereditary tyrosinemia in a French Canadian isolate. Am J Hum Genet. 1969 Jan;21(1):36–45. [PubMed]
  • John SW, Rozen R, Laframboise R, Laberge C, Scriver CR. Novel PKU mutation on haplotype 2 in French-Canadians. Am J Hum Genet. 1989 Dec;45(6):905–909. [PubMed]
  • John SW, Rozen R, Scriver CR, Laframboise R, Laberge C. Recurrent mutation, gene conversion, or recombination at the human phenylalanine hydroxylase locus: evidence in French-Canadians and a catalog of mutations. Am J Hum Genet. 1990 May;46(5):970–974. [PubMed]
  • Rozen R, Schwartz RH, Hilman BC, Stanislovitis P, Horn GT, Klinger K, Daigneault J, De Braekeleer M, Kerem B, Tsui L, et al. Cystic fibrosis mutations in North American populations of French ancestry: analysis of Quebec French-Canadian and Louisiana Acadian families. Am J Hum Genet. 1990 Oct;47(4):606–610. [PubMed]
  • Kaplan F, Kokotsis G, DeBraekeleer M, Morgan K, Scriver CR. Beta-thalassemia genes in French-Canadians: haplotype and mutation analysis of Portneuf chromosomes. Am J Hum Genet. 1990 Jan;46(1):126–132. [PubMed]
  • Hechtman P, Kaplan F, Bayleran J, Boulay B, Andermann E, de Braekeleer M, Melançon S, Lambert M, Potier M, Gagné R, et al. More than one mutant allele causes infantile Tay-Sachs disease in French-Canadians. Am J Hum Genet. 1990 Nov;47(5):815–822. [PubMed]
  • Ma Y, Henderson HE, Murthy V, Roederer G, Monsalve MV, Clarke LA, Normand T, Julien P, Gagné C, Lambert M, et al. A mutation in the human lipoprotein lipase gene as the most common cause of familial chylomicronemia in French Canadians. N Engl J Med. 1991 Jun 20;324(25):1761–1766. [PubMed]
  • Mitchell GA, Brody LC, Sipila I, Looney JE, Wong C, Engelhardt JF, Patel AS, Steel G, Obie C, Kaiser-Kupfer M, et al. At least two mutant alleles of ornithine delta-aminotransferase cause gyrate atrophy of the choroid and retina in Finns. Proc Natl Acad Sci U S A. 1989 Jan;86(1):197–201. [PubMed]

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