Acute intermittent porphyria: prevalence of mutations in the porphobilinogen deaminase gene in blood donors in France

Nordmann, Y; Puy, Hervé; Silva, V. Da; Simonin, Sylvie; Robréau, Anne-Marie; Bonaïti, Catherine; Phung, L. N.; Deybach, Jean Charles

doi:10.1046/j.1365-2796.1997.00189.x

Cited by 120 publications

(70 citation statements)

References 12 publications

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“…Most individuals who inherit a mutation for an acute hepatic porphyria never have an acute attack. Penetrance in AIP appears to be higher within families, with estimates varying from about 10% to 50% (Anderson et al 2001;Andersson et al 2000a;Elder et al 1997;Schuurmans et al 2001), than is suggested by population studies (Nordmann et al 1997). In most European countries, acute attacks of porphyria occur in about 1À2 per 100 000 of the general population.…”

Section: Molecular Genetics and Pathogenesismentioning

confidence: 98%

“…If, within these families, only 10% of those who inherit AIP ever develop symptoms, the derived prevalence of individuals with AIP mutations is about 1 in 7 500 of the general population. However, studies of blood donors show a much higher prevalence of about 1 in 1500 (Nordmann et al 1997), suggesting that clinical penetrance is very low. As yet, there is little information on genetic or other factors that determine penetrance, although it has been suggested that some mutations may be associated with a higher penetrance than others (Andersson et al 2000a).…”

Section: Molecular Genetics and Pathogenesismentioning

confidence: 99%

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Molecular mechanisms of dominant expression in porphyria

Badminton

Elder

2005

J of Inher Metab Disea

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Partial deficiency of enzymes in the haem synthetic pathway gives rise to a group of seven inherited metabolic disorders, the porphyrias. Each deficiency is associated with a characteristic increase in haem precursors that correlates with the symptoms associated with individual porphyrias and allows accurate diagnosis. Two types of clinical presentation occur separately or in combination; acute life-threatening neurovisceral attacks and/or cutaneous symptoms. Five of the porphyrias are low-penetrance autosomal dominant conditions in which clinical expression results from additional factors that act by increasing demand for haem or by causing an additional decrease in enzyme activity or by a combination of these effects. These include both genetic and environmental factors. In familial porphyria cutanea tarda (PCTF), environmental factors that include alcohol, exogenous oestrogens and hepatotropic viruses result in inhibition of hepatic enzyme activity via a mechanism that involves excess iron accumulation. In erythropoietic protoporphyria (EPP), co-inheritance of a functional polymorphism in trans to a null ferrochelatase allele accounts for most clinically overt cases. In the autosomal dominant acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria), acute neurovisceral attacks occur in a minority of those who inherit one of these disorders. Although various exogenous (e.g. drugs, alcohol) and endogenous factors (e.g. hormones) have been identified as provoking acute attacks, these do not provide a full explanation for the low penetrance of these disorders. It seems probable that genetic background influences susceptibility to acute attacks, but the genes that are involved have not yet been identified.

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Section: Molecular Genetics and Pathogenesismentioning

confidence: 98%

Section: Molecular Genetics and Pathogenesismentioning

confidence: 99%

Molecular mechanisms of dominant expression in porphyria

Badminton

Elder

2005

J of Inher Metab Disea

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“…AIP is the most common of the acute hepatic porphyrias, and the prevalence of PBGD gene defects has been estimated at 0.6 per 1,000 in the French Caucasian population (Nordmann et al 1997). PBGD is encoded by a single 11-kb gene located in chromosomal region 11q24.1→11q24.2 (Namba et al 1991).…”

Section: Introductionmentioning

confidence: 99%

Exon 1 donor splice site mutations in the porphobilinogen deaminase gene in the non-erythroid variant form of acute intermittent porphyria

et al. 1998

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Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by a partial defect of the heme biosynthesis enzyme, porphobilinogen deaminase (PBGD). PBGD is encoded by two distinct mRNA species expressed in a tissue-specific manner from a single gene. One transcript is expressed in erythroid tissues, while the housekeeping transcript is expressed in all tissues. In classical AIP (95% of cases) the housekeeping and the erythroid-specific enzymes both have half-normal activity in erythroid and non-erythroid tissues, whereas in the variant non-erythroid form of the disease the enzymatic defect is present only in non-erythroid cells. A large allelic heterogeneity of mutations (n>135) has been demonstrated in classical AIP, but to date only three different mutations have been characterized in the non-erythroid variant form of AIP. We describe the molecular abnormalities responsible for the non-erythroid variant form of AIP in two French and two German unrelated AIP patients with normal PBGD activity in the erythrocytes. Three different splicing defects located in the intron 1 donor splice site were identified: a 33+1 g-->a mutation, previously described in a Dutch family, was found in two patients; two novel mutations (33+2 t-->a, 33+5 c-->g) affected the two remaining patients. All the mutations resulted in the activation of a cryptic splice site 67 bp downstream in intron 1, leading to a frameshift and a premature stop codon in exon 4. Mutations in the exon 1 donor splice site are involved in eight of the nine non-erythroid variant AIP families reported in the literature. These data show that most mutations causing the non-erythroid variant AIP are exon 1 splice defects, in contrast with classical AIP, where missense mutations are chiefly involved. Moreover, the allelic heterogeneity of PBGD gene defects causing the non-erythroid variant AIP is demonstrated, with five different mutations identified. These mutations could be easily detected by a single denaturing gradient gel electrophoresis which also allows the presymptomatic detection of gene carriers in the affected families.

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“…Mutations in and around exon 1, of which four have been identified, are responsible for the uncommon variant of AIP in which only the ubiquitous isoenzyme is affected -erythrocyte PBG deaminase activity being normal. The extensive allelic heterogeneity of AIP, low de novo mutation rate, occasional sporadic presentation, and the rare occurrence of a severe homozygous or compound heterozygous variant (5) are all consistent with evidence that the minimum prevalence of AIP mutations in European populations is about 1 in 1500 (6).…”

Section: Acute Intermittent Porphyriamentioning

confidence: 66%

Update on enzyme and molecular defects in porphyria

Elder

1998

Photoderm Photoimm Photomed

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Each porphyria results from decreased activity of one of the enzymes of haem biosynthesis. The molecular basis of enzyme deficiencies in acute intermittent porphyria (AIP), variegate porphyria (VP) and congenital erythropoietic porphyria (CEP) is outlined. All three conditions show extensive allelic heterogeneity. In the autosomal dominant disorders, AIP and VP, no genotype/phenotype correlations have been demonstrated, and the explanation for their low clinical penetrance remains uncertain. In AIP and VP, mutational analysis is superior to biochemical methods for screening families for latent porphyria. In the autosomal recessive condition, CEP, there is some genotype/phenotype correlation -one common mutation (C73R) being associated with severe disease in homozygotes. Porphyria cutanea tarda (PCT) is not a simple monogenic disorder.

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Acute intermittent porphyria: prevalence of mutations in the porphobilinogen deaminase gene in blood donors in France

Cited by 120 publications

References 12 publications

Molecular mechanisms of dominant expression in porphyria

Molecular mechanisms of dominant expression in porphyria

Exon 1 donor splice site mutations in the porphobilinogen deaminase gene in the non-erythroid variant form of acute intermittent porphyria

Update on enzyme and molecular defects in porphyria

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