Hereditary Tyrosinemia Type I: Lack of Correlation between Clinical Findings and Amount of Immunoreactive Fumarylacetoacetase Protein

Kvittingen, E. A.; Rootwelt, Helge; Dam, Tijtje van; Faassen, Henk van; Berger, Ruud

doi:10.1203/00006450-199201000-00008

Cited by 18 publications

(9 citation statements)

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“…Distinction between acute and chronic tyrosinemia has been claimed on the basis of residual FAH activity and the amount of immunoreactive FAH protein by some investigators (3), but this has not been observed by us in previous studies (4 …”

Section: Introductionmentioning

confidence: 37%

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Hereditary tyrosinemia type I. Self-induced correction of the fumarylacetoacetase defect.

Kvittingen¹,

Rootwelt²,

Brandtzæg³

et al. 1993

J. Clin. Invest.

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Section: Introductionmentioning

confidence: 37%

“…Subcellular fractionation on fresh liver tissue (from patient 2) was performed by differential centrifugation as described by de Duve (7). Western blots were run as previously reported (4,8).…”

Section: Methodsmentioning

confidence: 99%

Hereditary tyrosinemia type I. Self-induced correction of the fumarylacetoacetase defect.

Kvittingen¹,

Rootwelt²,

Brandtzæg³

et al. 1993

J. Clin. Invest.

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“…Our results indicate substantial molecular and biochemical heterogeneity in HT 1. Four variants, summarized in Table I, (36).…”

Section: Discussionmentioning

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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“…However, further studies are necessary to elucidate the mechanism underlying the relative sensitivity of the kidney to HGA-induced damage. Based on our findings, we speculate that the liver failure, which is the predominant feature and main cause of death in patients diagnosed with the acute form of HT1 (2) that is often accompanied by complete absence of FAH protein (25,26), is caused by exposure to relatively high amounts of FAA. It is likewise plausible that renal tubular dysfunction, which is the most common presentation of the disease in patients with the chronic form of HT1 (2) and accompanied by residual FAH immunoreactivity (25,26), is the consequence of exposure to relatively low doses of FAA.…”

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confidence: 99%

Kidneys of Mice With Hereditary Tyrosinemia Type I Are Extremely Sensitive to Cytotoxicity

et al. 2006

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ABSTRACT:Children with hereditary tyrosinemia type 1 (HT1) suffer from liver failure, renal tubular dysfunction, and rickets. The disease is caused by deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme of tyrosine catabolism, and leads to accumulation of the toxic substrate fumarylacetoacetate (FAA) in hepatocytes and renal proximal tubular cells. Patients are treated with 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3 cyclohexanedione (NTBC), which prevents accumulation of FAA by blocking an enzyme upstream of FAH. Liver transplantation is performed when patients do not respond to NTBC or develop hepatocellular carcinoma. This reduces the tyrosine load for the kidney but does not abolish renal exposure to locally produced FAA. To investigate the pathogenesis of liver and kidney damage induced by tyrosine metabolites, we challenged FAH

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Hereditary Tyrosinemia Type I: Lack of Correlation between Clinical Findings and Amount of Immunoreactive Fumarylacetoacetase Protein

Abstract: [43][44][45][46] 1992)

Cited by 18 publications

References 5 publications

Hereditary tyrosinemia type I. Self-induced correction of the fumarylacetoacetase defect.

Hereditary tyrosinemia type I. Self-induced correction of the fumarylacetoacetase defect.

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

Kidneys of Mice With Hereditary Tyrosinemia Type I Are Extremely Sensitive to Cytotoxicity

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