Abstract
The complete fumarylacetoacetate hydrolase (FAH) genotype of probands of thirteen unrelated families with hereditary tyrosinemia type 1 (HT 1) was established. The screening was performed by analysis of exons 2–14 of the FAH gene by using the polymerase chain reaction (PCR) and of the mRNA by reverse transcription/PCR. Nine different mutations were identified, of which six are novel. Three mutations involve consensus sequences for correct splicing, viz. IVS 6-1 (g-t), IVS 7-1 (g-a) and IVS 12+5 (g-a). Two missense mutations (C193R and G369V) and three nonsense mutations (R237X, E357X and E364X) were found. One silent mutation N232N was associated with the skipping of exon 8 from the FAH mRNA. Analysis of the effect of the respective mutations on the FAH mRNA showed a strong reduction of FAH mRNA levels in association with the nonsense mutations, and normal levels with the missense mutations. The splice consensus mutations give deletions of complete or small parts of exon sequences from the FAH mRNA. Data suggest a founder effect for several of the mutations, with a frequency for both the IVS 6-1 (g-t) and IVS 12+5 (g-a) mutations of approximately 30% in the HT 1 probands. No strict correlation between genotype and phenotype, i.e. the acute, subacute or chronic form of HT 1, was evident.
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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
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
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 (abstract). Pediatr Res 24:266
DeBraekeleer MJ, Larochelle J (1990) Genetic epidemiology of hereditary tyrosinemia in Quebec and in Saguenay-Lac-St Jean. Am J Hum Genet 47:302–307
Demers SI, Phaneuf D, Tanguay RM (1994) Hereditary tyrosinemia type I: strong association with haplotype 6 in French Canadians permits simple carrier detection and prenatal diagnosis. Am J Hum Genet 55:327–333
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
Grompe M, Al-Dhalimy M (1993) Mutations of the fumarylacetoacetate hydrolase gene in four patients with tyrosinemia, type I. Hum Mutat 2:85–93
Grompe M, St.-Louis M, Demers SI, Al-Dhalimy M, Leclerc B, Tanguay RM (1994) A single mutation of the fumarylacetoacetate hydrolase gene in French Canadians with hereditary tyrosinemia type I. N Engl J Med 331:353–357
Kvittingen EA, Rootwelt H, Brandzaeg P, Bergan A, Berger R (1993) Hereditary tyrosinemia type I, self induced correction of the fumarylacetoacetase defect. J Clin Invest 91:1816–1821
Kvittingen EA, Rootwelt H, Berger R, Brandtzaeg P (1994) Selfinduced correction of the genetic defect in tyrosinemia type I. J Clin Invest 94:1657–1661
Labelle Y, Phaneuf D, Leclerc B, Tanguay RM (1993) Characterization of the human fumarylacetoacetae hydrolase gene and identification of a missense mutation abolishing enzymatic activity. Hum Mol Genet 2:941–946
Laberge C (1969) Hereditary tyrosinemia in a French Canadian isolate. Am J Hum Genet 21:36–45
Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T (1986) Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci USA 86:2766–2770
Phaneuf D, Labelle Y, Bérubé D, Arden K, Cavenee W, Gagné R, Tanguay RM (1991) Cloning and expression of the cDNA encoding human furmarylacetoacetate hydrolase, the enzyme deficient in hereditary tyrosinemia: assignment of the gene to chromosome 15. Am J Hum Genet 48:525–535
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
Ploos van Amstel JK, Jansen RPM, Verjaal M, Berg IET van den, Berger R (1994) Prenatal diagnosis of type I hereditary tyrosinemia. Lancet 344:336
Rootwelt H, Berger R, Gray G, Kelly DA, Coskun T, Kvittingen EA (1994a) Novel splice, missense, and nonsense mutations in the fumarylacetoacetase gene causing tyrosinemia type 1. Am J Hum Genet 55:653–658
Rootwelt H, Kirstensen T, Berger R, Hoeie K, Kvittingen EA (1994b) Tyrosinemia type 1- complex splicing defects and a missense mutation in the fumarylacetoacetase gene. Hum Genet 94:235–239
Rootwelt H, Chou J, Gahl WA, Berger R, Coskun T, Brodtkorb E, Kvittingen EA (1994c) Two missense mutations causing tyrosinemia type 1 with presence and absence of immunoreactive fumarylacetoacetase. Hum Genet 93:615–619
Rootwelt H, Brodtkorb E, Kvittingen EA (1994d) Identification of a frequent pseudodeficiency mutation in the fumarylacetoacetase gene, with implications for diagnosis of tyrosinemia type I. Am J Hum Genet 55:1122–1127
St.-Louis M, Leclerc B, Laine J, Salo MK, Holmberg C, Tanguay RM (1994) Identification of a stop mutation in five Finnish patients suffering from hereditary tyrosinemia type I. Hum Mol Genet 3:69–72
Saiki RK, Sharf S, Faloona F, Mullis KB, Horn GT, Ehrlich MA, Arnheim N (1985) Enzymatic amplification of beta globulin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science 230:1350–1354
Weinberg AG, Mize CE, Vorthen HG (1976) Occurrence of hepatoma in chronic form of hereditary tyrosinemia. J Pediatr 88:434–438
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van Amstel, J.K.P., Bergman, A.J.I.W., van Beurden, E.A.C.M. et al. Hereditary tyrosinemia type 1: novel missense, nonsense and splice consensus mutations in the human fumarylacetoacetate hydrolase gene; variability of the genotype-phenotype relationship. Hum Genet 97, 51–59 (1996). https://doi.org/10.1007/BF00218833
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DOI: https://doi.org/10.1007/BF00218833