The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH

Gouya, Laurent; Puy, Hervé; Robréau, Anne-Marie; Bourgeois, Monique; Lamoril, J.; Silva, Vasco Da; Grandchamp, Bernard; Deybach, Jean‐Charles

doi:10.1038/ng809

Cited by 238 publications

(220 citation statements)

References 8 publications

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“…Ferrochelatase DNA analysis in ten patients showed that each was heterozygous for a mutation in the ferrochelatase gene that caused splicing abnormality in six, frame shift or nonsense in three, and missense in one; nine patients also had a polymorphism in the other ferrochelatase allele (IVS3-48c) that caused low expression of the gene. [1][2][3] The diagnosis of EPP liver disease was confirmed by examination of the explants, which were enlarged and black in color, and with most having micronodular cirrhosis ( Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

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Liver transplantation for erythropoietic protoporphyria liver disease

et al. 2005

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In erythropoietic protoporphyria (EPP), there is excessive production of protoporphyrin, primarily in the bone marrow, resulting in increased biliary excretion of this heme precursor. Some patients will develop progressive liver disease that may ultimately require liver transplantation. However, excessive production of protoporphyrin by the bone marrow continues after transplantation, which may cause recurrent disease in the allograft. This study was performed to define post-transplant survival, the risk of recurrent disease, and specific management issues in patients transplanted for EPP liver disease. The patients studied consisted of twelve males and eight females, with an average age of 31 (range, 13-56) years at the time of transplantation. The estimated maximum MELD score prior to transplant was 21 (range, 15-29). Unique complications in the perioperative period were light induced tissue damage in four patients and neuropathy in six, requiring prolonged mechanical ventilation in four. Patient and graft survival rates were 85% at 1 year, 69% at 5 years, and 47% at 10 years. Recurrent EPP liver disease occurred in 11 of 17 patients (65%) who survived more than 2 months. Three patients were retransplanted at 1.8, 12.6, and 14.5 years after the initial transplant for recurrent EPP liver disease. In conclusion, the 5-year patient survival rate in patients transplanted for EPP liver disease is good, but the recurrence of EPP liver disease appears to diminish long term graft and patient survival. (Liver Transpl 2005;11:1590-1596.)

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Section: Resultsmentioning

confidence: 99%

“…[1][2][3] Patients with EPP have excessive production of protoporphyrin, primarily in the bone marrow, resulting in increased biliary excretion of this compound. 4 The major clinical manifestation in EPP is photosensitivity, which is caused by the photo-active damage to skin by protoporphyrin.…”

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confidence: 99%

Liver transplantation for erythropoietic protoporphyria liver disease

et al. 2005

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“…[2Fe-2S] clusters have been identified in animal ferrochelatases (4,5), in the yeast Schizosaccharomyces pombe (6), and in the bacterial species Caulobacter crescentus and Mycobacterium tuberculosis (7), but their roles remain elusive. Genetic defects in mammalian ferrochelatase cause a metabolic disease, erythropoietic protoporphyria (8,9).…”

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confidence: 99%

Probing the Active Site Loop Motif of Murine Ferrochelatase by Random Mutagenesis

Shi

Ferreira

2004

Journal of Biological Chemistry

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Ferrochelatase catalyzes the terminal step of the heme biosynthetic pathway by inserting ferrous iron into protoporphyrin IX. A conserved loop motif was shown to form part of the active site and contact the bound porphyrin by molecular dynamics calculations and structural analysis. We applied a random mutagenesis approach and steady-state kinetic analysis to assess the role of the loop motif in murine ferrochelatase function, particularly with respect to porphyrin interaction.

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“…(7,27) EPP inherited as an autosomal dominant disorder also shows incomplete penetrance since affected and normal individuals (both carrying the mutation) are observed in the same family. (28) The authors suggest that penetrance is modulated by an intronic single nucleotide polymorphism (SNP) at a cryptic splice site on the wild-type allele, leading to production of an aberrant transcript that is degraded and, therefore, results in near absence of the ferrochelatase enzyme. Individuals carrying the dominant mutation as well as the intronic SNP will, therefore, show a total absence of the ferrochelatase enzyme, while those with the mutation but no intronic SNP will have reduced levels.…”

Section: Molecular Basis Of Ip-vementioning

confidence: 99%

Incomplete penetrance and variable expressivity: is there a microRNA connection?

et al. 2009

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Incomplete penetrance and variable expressivity are non‐Mendelian phenomena resulting in the lack of correlation between genotype and phenotype. Not withstanding the diversity in mechanisms, differential expression of homologous alleles within cells manifests as variations in penetrance and expressivity of mutations between individuals of the same genotype. These phenomena are seen most often in dominantly inherited diseases, implying that they are sensitive to concentration of the gene product. In this framework and the advances in understanding the role of microRNA (miRNA) in fine‐tuning gene expression at translational level, we propose miRNA‐mediated regulation as a mechanism for incomplete penetrance and variable expressivity. The presence of miRNA binding sites at 3′ UTR, co‐expression of target gene–miRNA pairs for genes showing incomplete penetrance and variable expressivity derived from available data lend support to our hypothesis. Single nucleotide polymorphisms in the miRNA target site facilitate the implied differential targeting of the transcripts from homologous alleles.

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The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH

Cited by 238 publications

References 8 publications

Liver transplantation for erythropoietic protoporphyria liver disease

Liver transplantation for erythropoietic protoporphyria liver disease

Probing the Active Site Loop Motif of Murine Ferrochelatase by Random Mutagenesis

Incomplete penetrance and variable expressivity: is there a microRNA connection?

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