Mspl RFLP in the human fumarylacetoacetate hydrolase (FAH) gene

Demers, Sylvie I.; Tanguay, Robert M.

doi:10.1093/nar/19.24.6971

Cited by 4 publications

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“…Introduction of the human FAH cDNA into CV-1 monkey kidney cells resulted in the synthesis of a fully functional enzyme, indicating that the encoded sequence contained all the genetic information necessary for the hydrolytic activity ( 14). We mapped the structural gene for human FAH to the long arm of chromosome 15 in the region q23-25 (14) and identified restriction site polymorphisms at the FAH locus in normal humans (16)(17)(18)(19) Sequence analysis ofthis cDNA identified an A47 to T transversion that predicted an asparagine to isoleucine substitution at codon 16 (N161). Amplification and sequencing of this specific region on genomic DNA suggested that the patient is a genetic compound.…”

Section: Introductionmentioning

confidence: 99%

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

Phaneuf

Lambert²,

Laframboise³

et al. 1992

J. Clin. Invest.

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IntroductionType 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 asparagine'6 with isoleucine (N161), was identified. This patient was heterozygous as shown by direct sequencing of the amplified region and hybridization with allele-specific oligonucleotide probes. The N161 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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Section: Introductionmentioning

confidence: 99%

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

Phaneuf

Lambert²,

Laframboise³

et al. 1992

J. Clin. Invest.

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The human fumarylacetoacetase gene: characterisation of restriction fragment length polymorphisms and identification of haplotypes in tyrosinemia type 1 and pseudodeficiency

et al. 1992

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Deficiency of human fumarylacetoacetase (FAH) activity results in hereditary tyrosinemia type I. Using the restriction enzymes BglII, KpnI and StuI and a 1.3-kb cDNA probe for the FAH gene, we have found 6 restriction fragment length polymorphisms (RFLPs). These RFLPs were utilised in 3 tyrosinemia families in which one or both parents are carriers of both a tyrosinemia and a pseudodeficiency gene for FAH. Full information was obtained in two of these families. The polymorphisms identified 6 haplotypes. The haplotype distribution was significantly different in 32 unrelated tyrosinemia patients compared with a reference population of 100 individuals. The combined polymorphism information content was 0.77.

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Therapeutic trials in the murine model of hereditary tyrosinaemia type I: A progress report

Grompe

Overturf

Al‐Dhalimy

et al. 1998

J of Inher Metab Disea

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We have studied a knockout mouse with fumarylacetoacetate hydrolase (FAH) deficiency as a model of human hereditary tyrosinaemia type (I (HT1). These mice have a phenotype very similar to the human disease, which is characterized by acute hepatic failure, renal tubular disease and hepatocarcinoma. We have previously reported on the efficacy of 2-(2-nitro-4-trifluoromethylbenzyol)-1,3-cyclohexanedione (NTBC) in preventing acute liver disease in HT1 mice. Here we present a progress report on long-term follow up (> 1 year) of high-dose NTBC therapy in combination with tyrosine restriction. In vivo retroviral gene therapy was also effective in abolishing the acute liver failure of HT1. Retrovirally treated mice remained completely healthy and active for 12 months after retroviral gene transfer. However, hepatocarcinoma developed in 2/3 treated animals after 1 year. Southern blot analysis showed that the tumours did not arise from retrovirally transduced hepatocytes but from non-corrected FAH-deficient cells. These results highlight the extreme danger for tumour formation in HT1 and indicate the need for improved gene therapy that leads to the elimination of endogenous FAH-deficient liver cells.

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Mspl RFLP in the human fumarylacetoacetate hydrolase (FAH) gene

Cited by 4 publications

References 0 publications

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

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

The human fumarylacetoacetase gene: characterisation of restriction fragment length polymorphisms and identification of haplotypes in tyrosinemia type 1 and pseudodeficiency

Therapeutic trials in the murine model of hereditary tyrosinaemia type I: A progress report

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