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• W2093804948 abstract "Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis that results from a partial deficiency of ferrochelatase (FECH). Recently, we have shown that the inheritance of the common hypomorphic IVS3-48C allele trans to a deleterious mutation reduces FECH activity to below a critical threshold and accounts for the photosensitivity seen in patients. Rare cases of autosomal recessive inheritance have been reported. We studied a cohort of 173 white French EPP families and a group of 360 unrelated healthy subjects from four ethnic groups. The prevalences of the recessive and dominant autosomal forms of EPP are 4% (95% confidence interval 1–8) and 95% (95% confidence interval 91–99), respectively. In 97.9% of dominant cases, an IVS3-48C allele is coinherited with the deleterious mutation. The frequency of the IVS3-48C allele differs widely in the Japanese (43%), southeast Asian (31%), white French (11%), North African (2.7%), and black West African (<1%) populations. These differences can be related to the prevalence of EPP in these populations and could account for the absence of EPP in black subjects. The phylogenic origin of the IVS3-48C haplotypes strongly suggests that the IVS3-48C allele arose from a single recent mutational event. Estimation of the age of the IVS3-48C allele from haplotype data in white and Asian populations yields an estimated age three to four times younger in the Japanese than in the white population, and this difference may be attributable either to differing demographic histories or to positive selection for the IVS3-48C allele in the Asian population. Finally, by calculating the KAKS ratio in humans and chimpanzees, we show that the FECH protein sequence is subject to strong negative pressure. Overall, EPP looks like a Mendelian disorder, in which the prevalence of overt disease depends mainly on the frequency of a single common single-nucleotide polymorphism resulting from a unique mutational event that occurred 60,000 years ago. Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis that results from a partial deficiency of ferrochelatase (FECH). Recently, we have shown that the inheritance of the common hypomorphic IVS3-48C allele trans to a deleterious mutation reduces FECH activity to below a critical threshold and accounts for the photosensitivity seen in patients. Rare cases of autosomal recessive inheritance have been reported. We studied a cohort of 173 white French EPP families and a group of 360 unrelated healthy subjects from four ethnic groups. The prevalences of the recessive and dominant autosomal forms of EPP are 4% (95% confidence interval 1–8) and 95% (95% confidence interval 91–99), respectively. In 97.9% of dominant cases, an IVS3-48C allele is coinherited with the deleterious mutation. The frequency of the IVS3-48C allele differs widely in the Japanese (43%), southeast Asian (31%), white French (11%), North African (2.7%), and black West African (<1%) populations. These differences can be related to the prevalence of EPP in these populations and could account for the absence of EPP in black subjects. The phylogenic origin of the IVS3-48C haplotypes strongly suggests that the IVS3-48C allele arose from a single recent mutational event. Estimation of the age of the IVS3-48C allele from haplotype data in white and Asian populations yields an estimated age three to four times younger in the Japanese than in the white population, and this difference may be attributable either to differing demographic histories or to positive selection for the IVS3-48C allele in the Asian population. Finally, by calculating the KAKS ratio in humans and chimpanzees, we show that the FECH protein sequence is subject to strong negative pressure. Overall, EPP looks like a Mendelian disorder, in which the prevalence of overt disease depends mainly on the frequency of a single common single-nucleotide polymorphism resulting from a unique mutational event that occurred 60,000 years ago. Complex phenotype/genotype relationships in simple Mendelian disorders have often been attributed to environmental factors or to modifier genes that modulate the clinical expression of a gene defect at a major locus. An alternative hypothesis is that, in some dominantly inherited disorders, clinical manifestations are not simply a matter of haploinsufficiency and that some additional deficiency may be necessary for the phenotype to be expressed (Delaunay Delaunay, 2002Delaunay J Molecular basis of red cell membrane disorders.Acta Haematol. 2002; 108: 210-218Crossref PubMed Scopus (75) Google Scholar; Emison et al. Emison et al., 2005Emison ES McCallion AS Kashuk CS Bush RT Grice E Lin S Portnoy ME Cutler DJ Green ED Chakravarti A A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk.Nature. 2005; 434: 857-863Crossref PubMed Scopus (381) Google Scholar). In these disorders, slight differences in the expression of the normal allele in trans to the mutated allele may have a major impact on the clinical expression of the disease by reducing gene expression below a critical threshold. The penetrance of a dominant mutation may thus be modulated by functional polymorphisms occurring at the same locus. Erythropoietic protoporphyria (EPP) (MIM 177000) is an inherited disorder due to a partial deficiency of ferrochelatase (FECH) (EC 4.99.1.1.), the final enzyme in the heme biosynthesis pathway (Anderson et al. Anderson et al., 2001Anderson KE Sassa S Bishop DF Desnick RJ Disorders of heme biosynthesis: X-linked sideroblastic anemia and the porphyrias.in: Scriver CR Beaudet AL Sly WS Valle D The metabolic and molecular basis of inherited disease. 8th ed. McGraw-Hill, New York2001: 2961-3062Google Scholar). FECH is an inner membrane mitochondrial enzyme that catalyzes the insertion of ferrous iron into protoporphyrin IX to form heme. FECH deficiency in bone marrow erythroid cells is responsible for the overproduction and accumulation of protoporphyrin IX in erythrocytes, which leads to a secondary accumulation of protoporphyrin in the plasma, skin, bile, and feces (Anderson et al. Anderson et al., 2001Anderson KE Sassa S Bishop DF Desnick RJ Disorders of heme biosynthesis: X-linked sideroblastic anemia and the porphyrias.in: Scriver CR Beaudet AL Sly WS Valle D The metabolic and molecular basis of inherited disease. 8th ed. McGraw-Hill, New York2001: 2961-3062Google Scholar). The most common clinical manifestation is lifelong acute photosensitivity of the skin in response to exposure to the sun, which develops early in childhood. Although EPP is generally a benign condition, hepatic complications, such as cholelithiasis or, in rare cases (∼2%), cirrhosis and even rapidly fatal liver disease, may occur (Bloomer Bloomer, 1988Bloomer JR The liver in protoporphyria.Hepatology. 1988; 8: 402-407Crossref PubMed Scopus (101) Google Scholar; Doss and Frank Doss and Frank, 1989Doss MO Frank M Hepatobiliary implications and complications in protoporphyria, a 20-year study.Clin Biochem. 1989; 22: 223-229Crossref PubMed Scopus (111) Google Scholar; Todd Todd, 1994Todd DJ Erythropoietic protoporphyria.Br J Dermatol. 1994; 131: 751-766Crossref PubMed Scopus (167) Google Scholar; Meerman Meerman, 2000Meerman L Erythropoietic protoporphyria: an overview with emphasis on the liver.Scand J Gastroenterol Suppl. 2000; : 79-85PubMed Google Scholar). EPP cases have been reported in Europe, the United States, and Japan. So far, to our knowledge, no case of EPP has been reported in a black African subject. More than 85 mutations in the FECH gene, including missense, nonsense, splicing, deletions, and insertions, have been identified in EPP families (fig. 1A) (Rüfenacht et al. Rüfenacht et al., 1998Rüfenacht UB Gouya L Schneider-Yin X Puy H Schafer BW Aquaron R Nordmann Y Minder EI Deybach JC Systematic analysis of molecular defects in the ferrochelatase gene from patients with erythropoietic protoporphyria.Am J Hum Genet. 1998; 62: 1341-1352Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar; Yotsumoto et al. Yotsumoto et al., 2001Yotsumoto S Shimada S Terasaki K Taketani S Kobayashi K Saheki T Kanzaki T A novel A(-4)-to-G acceptor splice site mutation leads to three bases insertion in ferrochelatase mRNA in a patient with erythropoietic protoporphyria.J Invest Dermatol. 2001; 117: 159-161Crossref PubMed Google Scholar; Chen et al. Chen et al., 2002Chen FP Risheg H Liu Y Bloomer J Ferrochelatase gene mutations in erythropoietic protoporphyria: focus on liver disease.Cell Mol Biol (Noisy-le-grand). 2002; 48: 83-89PubMed Google Scholar; Yasui et al. Yasui et al., 2002Yasui Y Muranaka S Tahara T Shimizu R Watanabe S Horie Y Nanba E Uezato H Takamiyagi A Taketani S Akagi R A new ferrochelatase mutation combined with low expression alleles in a Japanese patient with erythropoietic protoporphyria.Clin Sci (Lond). 2002; 102: 501-506Crossref PubMed Scopus (12) Google Scholar; Wiman et al. Wiman et al., 2003Wiman A Floderus Y Harper P Novel mutations and phenotypic effect of the splice site modulator IVS3-48C in nine Swedish families with erythropoietic protoporphyria.J Hum Genet. 2003; 48: 70-76Crossref PubMed Scopus (32) Google Scholar; Onaga et al. Onaga et al., 2004Onaga Y Ido A Uto H Hasuike S Kusumoto K Moriuchi A Numata M Nagata K Hori T Hayashi K Tsubouchi H Hypermethylation of the wild-type ferrochelatase allele is closely associated with severe liver complication in a family with erythropoietic protoporphyria.Biochem Biophys Res Commun. 2004; 321: 851-858Crossref PubMed Scopus (17) Google Scholar; Whatley et al. Whatley et al., 2004Whatley SD Mason NG Khan M Zamiri M Badminton MN Missaoui WN Dailey TA Dailey HA Douglas WS Wainwright NJ Elder GH Autosomal recessive erythropoietic protoporphyria in the United Kingdom: prevalence and relationship to liver disease.J Med Genet. 2004; 41: e105Crossref PubMed Scopus (65) Google Scholar; Human Gene Mutation Database). EPP is characterized by a high allele heterogeneity, although some founder mutations have been reported in Swiss patients (Rüfenacht et al. Rüfenacht et al., 1998Rüfenacht UB Gouya L Schneider-Yin X Puy H Schafer BW Aquaron R Nordmann Y Minder EI Deybach JC Systematic analysis of molecular defects in the ferrochelatase gene from patients with erythropoietic protoporphyria.Am J Hum Genet. 1998; 62: 1341-1352Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). Most individuals who are heterozygous for these mutations are asymptomatic, despite having FECH activity levels that are only half the normal value (Nordmann and Deybach Nordmann and Deybach, 1990Nordmann Y Deybach JC Human hereditary porphyrias.in: Dailey HA Biosynthesis of heme and chlorophylls. McGraw-Hill, New York1990: 491-542Google Scholar). For protoporphyrin to accumulate sufficiently to cause photosensitivity, FECH activity has to fall below a critical threshold of ∼35% of the normal level (Bonkowsky et al. Bonkowsky et al., 1975Bonkowsky HL Bloomer JR Ebert PS Mahoney MJ Heme synthetase deficiency in human protoporphyria: demonstration of the defect in liver and cultured skin fibroblasts.J Clin Invest. 1975; 56: 1139-1148Crossref PubMed Scopus (186) Google Scholar; Rossi et al. Rossi et al., 1988Rossi E Costin KA Garcia-Webb P Ferrochelatase activity in human lymphocytes, as quantified by a new high-performance liquid-chromatographic method.Clin Chem. 1988; 34: 2481-2485PubMed Google Scholar; Nordmann and Deybach Nordmann and Deybach, 1990Nordmann Y Deybach JC Human hereditary porphyrias.in: Dailey HA Biosynthesis of heme and chlorophylls. McGraw-Hill, New York1990: 491-542Google Scholar). On the basis of enzymatic assays and molecular analysis in EPP families, two modes of inheritance have been proposed. In rare cases, the disorder is transmitted as an autosomal recessive trait, with both parents transmitting a molecular defect to the affected children, who typically have a residual lymphocyte FECH activity of <10% of normal (Deybach et al. Deybach et al., 1986Deybach JC Da Silva V Pasquier Y Nordmann Y Ferrochelatase in human erythropoietic protoporphyria: the first case of a homozygous form of the enzyme deficiency.in: Nordmann Y Porphyrines and porphyries. John Libbey, Paris1986: 163-173Google Scholar; Norris et al. Norris et al., 1990Norris PG Nunn AV Hawk JL Cox TM Genetic heterogeneity in erythropoietic protoporphyria: a study of the enzymatic defect in nine affected families.J Invest Dermatol. 1990; 95: 260-263Abstract Full Text PDF PubMed Google Scholar; Lamoril et al. Lamoril et al., 1991Lamoril J Boulechfar S de Verneuil H Grandchamp B Nordmann Y Deybach JC Human erythropoietic protoporphyria: two point mutations in the ferrochelatase gene.Biochem Biophys Res Commun. 1991; 181: 594-599Crossref PubMed Scopus (105) Google Scholar; Sarkany et al. Sarkany et al., 1994Sarkany RP Alexander GJ Cox TM Recessive inheritance of erythropoietic protoporphyria with liver failure.Lancet. 1994; 344: 958-959Abstract PubMed Scopus (21) Google Scholar; Goerz et al. Goerz et al., 1996Goerz G Bunselmeyer S Bolsen K Schurer NY Ferrochelatase activities in patients with erythropoietic protoporphyria and their families.Br J Dermatol. 1996; 134: 880-885Crossref PubMed Scopus (23) Google Scholar; Whatley et al. Whatley et al., 2004Whatley SD Mason NG Khan M Zamiri M Badminton MN Missaoui WN Dailey TA Dailey HA Douglas WS Wainwright NJ Elder GH Autosomal recessive erythropoietic protoporphyria in the United Kingdom: prevalence and relationship to liver disease.J Med Genet. 2004; 41: e105Crossref PubMed Scopus (65) Google Scholar). So far, to our knowledge, only seven cases of autosomal recessive transmission have been documented (Lamoril et al. Lamoril et al., 1991Lamoril J Boulechfar S de Verneuil H Grandchamp B Nordmann Y Deybach JC Human erythropoietic protoporphyria: two point mutations in the ferrochelatase gene.Biochem Biophys Res Commun. 1991; 181: 594-599Crossref PubMed Scopus (105) Google Scholar; Sarkany et al. Sarkany et al., 1994Sarkany RP Alexander GJ Cox TM Recessive inheritance of erythropoietic protoporphyria with liver failure.Lancet. 1994; 344: 958-959Abstract PubMed Scopus (21) Google Scholar; Poh-Fitzpatrick et al. Poh-Fitzpatrick et al., 2002Poh-Fitzpatrick MB Wang X Anderson KE Bloomer JR Bolwell B Lichtin AE Erythropoietic protoporphyria: altered phenotype after bone marrow transplantation for myelogenous leukemia in a patient heteroallelic for ferrochelatase gene mutations.J Am Acad Dermatol. 2002; 46: 861-866Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar; Whatley et al. Whatley et al., 2004Whatley SD Mason NG Khan M Zamiri M Badminton MN Missaoui WN Dailey TA Dailey HA Douglas WS Wainwright NJ Elder GH Autosomal recessive erythropoietic protoporphyria in the United Kingdom: prevalence and relationship to liver disease.J Med Genet. 2004; 41: e105Crossref PubMed Scopus (65) Google Scholar). In most cases, the inheritance of EPP is described as an autosomal dominant disorder with incomplete penetrance. We have recently demonstrated that patients with the dominant form usually share a hypomorphic allele that is common in the general population in trans to a rare loss-of-function allele (Went and Klasen Went and Klasen, 1984Went LN Klasen EC Genetic aspects of erythropoietic protoporphyria.Ann Hum Genet. 1984; 48: 105-117Crossref PubMed Scopus (115) Google Scholar; Gouya et al. Gouya et al., 1996Gouya L Deybach JC Lamoril J Da Silva V Beaumont C Grandchamp B Nordmann Y Modulation of the phenotype in dominant erythropoietic protoporphyria by a low expression of the normal ferrochelatase allele.Am J Hum Genet. 1996; 58: 292-299PubMed Google Scholar, Gouya et al., 1999Gouya L Puy H Lamoril J Da Silva V Grandchamp B Nordmann Y Deybach JC Inheritance in erythropoietic protoporphyria: a common wild-type ferrochelatase allelic variant with low expression accounts for clinical manifestation.Blood. 1999; 93: 2105-2110PubMed Google Scholar, Gouya et al., 2002Gouya L Puy H Robreau AM Bourgeois M Lamoril J Da Silva V Grandchamp B Deybach JC The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH.Nat Genet. 2002; 30: 27-28Crossref PubMed Scopus (219) Google Scholar). A common intronic SNP, IVS3-48C, is responsible for the low expression of the hypomorphic allele by modulating the use of a constitutive cryptic acceptor splice site; the aberrantly spliced mRNA is degraded by a nonsense-mediated decay mechanism, leading to a lower steady-state level of FECH mRNA. In overt cases, this low steady-state level of normal mRNA results in an additional FECH enzyme deficiency, which is necessary for protoporphyrin overproduction and photosensitivity to occur (Gouya et al. Gouya et al., 2002Gouya L Puy H Robreau AM Bourgeois M Lamoril J Da Silva V Grandchamp B Deybach JC The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH.Nat Genet. 2002; 30: 27-28Crossref PubMed Scopus (219) Google Scholar). In this article, we report our study of two large cohorts of white French (WF) EPP families and a control group of 360 unrelated healthy subjects from four different ethnic groups. We first established the relative prevalence of the autosomal recessive versus the dominant forms and, then, in the dominant form, we identified the different mechanisms that underlie the incomplete penetrance of FECH mutations. We then studied the IVS3-48T/C polymorphism in different populations, investigating the relationship between IVS3-48C allele prevalence and overt EPP occurrence. Finally, we focused our attention on the phylogenic origin of the IVS3-48C allele and estimated when the IVS3-48C allele first appeared. We investigated a first cohort of 241 subjects from 113 WF EPP families recruited at the Centre Français des Porphyries between 1990 and 2004 (fig. 2). The 241 subjects consisted of 113 overt patients with a typical history of skin photosensitivity and a high level of free protoporphyrin in their erythrocytes (32,443 ± 21,243 [mean ± SD] nM; normal <1,900 nM) plus 128 clinically unaffected relatives. We assayed peripheral lymphocyte FECH enzyme activity in 95 of the 113 overt patients. Family studies (nuclear or extended families) allowed us to perform an IVS3-48T/C segregation analysis in 53 cases. The second cohort consisted of 60 nuclear (n=25) or extended (n=35) French EPP families, who were recruited at the Centre Français des Porphyries between 1975 and 2000 and had well-documented clinical histories and FECH enzyme activity levels, which allowed us to assess the correlation between the IVS3-48C allele frequency and the prevalence of overt EPP. These families were independent of the 113 described above, and their EPP diagnosis was based on clinical data and the measurement of lymphocyte FECH activity (overt EPP patients, 1.5 ± 0.39 [mean ± SD] nM) and erythrocyte protoporphyrin levels (overt EPP patients, 36,840 ± 44,468 [mean ± SD] nM). No DNA was available from these subjects. Available for study were 361 subjects consisting of 60 probands, 152 relatives whose lymphocyte FECH activity was at least 50% below normal, and 149 relatives whose lymphocyte FECH activity was in the normal range. The 301 relatives were distributed across 100 different generations. Three hundred sixty subjects unrelated to EPP patients were studied: 80 WF; 75 North Africans (NA) originating from Algeria, Morocco, or Tunisia; 115 southeast Asians (SEA) originating from Vietnam, Cambodia, or Shanghai, China; and 100 black West Africans (WA) originating from Cameroon, the Ivory Coast, or Nigeria. These procedures involving human subjects were performed in accordance with the 1983 revision of the Declaration of Helsinki, and the study was approved by the Hospital Ethics Committee of Hôpital Ambroise Paré, in Paris. Genomic DNA was extracted from peripheral blood leukocytes with the use of a QIAamp DNA purification kit (Qiagen). All coding regions, the intron/exon junctions with 200–300 bp flanking sequence, 1.3 kb of 5′ noncoding region, and the two polyadenylation signal regions were PCR amplified and subjected to direct sequencing using fluorescent ddNTPs (BigDye) and an ABI Prism 3100 Genetic Analyzer (Applied Biosystems). Primers and conditions are available from the corresponding author on request. The presence or absence of mutations was confirmed by the sequencing of both strands. We also sequenced DNA samples from three chimpanzees (Pan troglodytes), using the same set of primers (GenBank accession number DQ149645). We analyzed the 12 intragenic SNPs distributed over the FECH gene: ss46563186, ss46563187, ss46563188, and rs17063905 are located in the promoter region; rs2269219 is in intron 1; ss46563189 is in intron 2; IVS3-48T/C (rs2272783) is in intron 3; ss46563190 is in intron 4; ss46563191 is in intron 5;1 ss46563192 and ss46563193 are in intron 9; and rs8339 is in the noncooling region of exon 11. Human FECH genomic DNA and cDNA are numbered in accordance with the reference sequences, with GenBank accession numbers AJ 250235 and NM000140, respectively, with the A of the ATG initiation codon shown as “+1.” The symbols used to designate genes in this article follow the guidelines of the HUGO Gene Nomenclature Committee (Povey et al. Povey et al., 2001Povey S Lovering R Bruford E Wright M Lush M Wain H The HUGO Gene Nomenclature Committee (HGNC).Hum Genet. 2001; 109: 678-680Crossref PubMed Scopus (372) Google Scholar). After PCR amplification of the appropriate fragments, PCR products were digested with HinfI, HaeII, DdeI, AluI, Cac8I, NlaIII, TseI, BstNI, BsrI, BsmAI, and TaqIα restriction enzymes. SNP genotyping of rs8339 was performed using denaturing gradient gel electrophoresis, as described elsewhere (Gouya et al. Gouya et al., 1999Gouya L Puy H Lamoril J Da Silva V Grandchamp B Nordmann Y Deybach JC Inheritance in erythropoietic protoporphyria: a common wild-type ferrochelatase allelic variant with low expression accounts for clinical manifestation.Blood. 1999; 93: 2105-2110PubMed Google Scholar). All primers and conditions are available on request. IVS3-48T/C data for the Japanese population were provided by Nakamura Yusuke (Human Genome Center, Institute of Medical Science, University of Tokyo) and are available in the dbSNP. Haplotypes were estimated from unphased genotypes by use of the expectation maximization (EM) algorithm included in the software package ARLEQUIN ver 2.000 (Schneider et al. Schneider et al., 1997Schneider S Kueffer J-M Roessli D Excoffier L Arlequin version 1.1: a software for population genetic data analysis. Genetics and Biometry Laboratory, University of Geneva, Geneva1997Google Scholar). Phylogenetic analysis of the individual haplotypes used the minimal spanning network included in ARLEQUIN. FECH activity was determined by fluorometric measurement of zinc-mesoporphyrin formation after incubation for 60 min at 37°C, as established by Li et al. (Li et al., 1987Li FM Lim CK Peters TJ An HPLC assay for rat liver ferrochelatase activity.Biomed Chromatogr. 1987; 2: 164-168Crossref PubMed Scopus (53) Google Scholar), but with some modifications. For routine assays, a peripheral lymphocyte homogenate was prepared in 50 mM Tris-HCl (pH 7.6) and 20% glycerol, and the protein concentration was measured using the Bradford method (Bio-Rad reagents). The reaction consisted of a 5-min preincubation at 37°C, with 200 μl of lymphocyte homogenate, 200 μl of incubation buffer (250 mM Tris-HCl [pH 7.6], 1% [v/v] Triton X-100, and 1.75 mM palmitic acid), and 40 μl of 0.5-mM mesoporphyrin (final concentration 43 μM). Then, 20 μl of 1-mM zinc acetate solution was added (final concentration 43 μM), and the incubation continued for a further 60 min. A blank was prepared without the cell homogenate. The reaction was stopped by the addition of a dimethyl sulfoxide/methanol mixture (30:70 [v/v]). After it was centrifuged, the supernatant was transferred to a fluorometry cell, and the fluorescence was measured at 580 nm, with an excitation wavelength of 410 nm. The enzymatic activity was expressed as nanomoles of zinc-mesoporphyrin formed per hour per milligram of protein at 37°C (normal value = 4.83 ± 0.91 [mean ± SD] nmol mesozinc/h/mg). The erythrocyte protoporphyrin was determined by standard methods (Deacon and Elder Deacon and Elder, 2001Deacon AC Elder GH ACP best practice no 165: front line tests for the investigation of suspected porphyria.J Clin Pathol. 2001; 54: 500-507Crossref PubMed Scopus (102) Google Scholar). The Student t test or the Mann-Whitney test was used to compare group means of continuous data. Standard deviations were calculated for group means. The genotype distribution of the 12 polymorphisms in the WF, WA, and SEA populations and for the IVS3-48T/C SNP in the NA population satisfied the Hardy-Weinberg equilibrium (χ2 test, P>.5). We performed a joint estimate of these quantities, using the method developed by Austerlitz et al. (Austerlitz et al., 2003Austerlitz F Kalaydjieva L Heyer E Detecting population growth, selection and inherited fertility from haplotypic data in humans.Genetics. 2003; 165: 1579-1586PubMed Google Scholar). This method provides a joint estimate of the age of the mutation—that is, the time elapsed since the appearance of the common ancestor of the mutation carriers in the population and the growth rate of the number of copies since this appearance. This common ancestor can be either a new mutant or a migrant who brought the gene into the population or the only individual who left offspring carrying this mutation in the present population because of a bottleneck. Four different populations were studied: the 80 WF subjects, the 92 Chinese from the SEA population, the 50 parents from 25 fully genotyped EPP families, and the 44 Japanese subjects from the International HapMap Project. We conducted a FECH molecular study on 113 overt EPP patients available between 1990 and 2004 from the Centre Français des Porphyries. Twenty-five of these EPP patients had already been studied and reported but were re-evaluated here for the IVS3-48T/C polymorphism (Lamoril et al. Lamoril et al., 1991Lamoril J Boulechfar S de Verneuil H Grandchamp B Nordmann Y Deybach JC Human erythropoietic protoporphyria: two point mutations in the ferrochelatase gene.Biochem Biophys Res Commun. 1991; 181: 594-599Crossref PubMed Scopus (105) Google Scholar; Rüfenacht et al. Rüfenacht et al., 1998Rüfenacht UB Gouya L Schneider-Yin X Puy H Schafer BW Aquaron R Nordmann Y Minder EI Deybach JC Systematic analysis of molecular defects in the ferrochelatase gene from patients with erythropoietic protoporphyria.Am J Hum Genet. 1998; 62: 1341-1352Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar; Gouya et al. Gouya et al., 1996Gouya L Deybach JC Lamoril J Da Silva V Beaumont C Grandchamp B Nordmann Y Modulation of the phenotype in dominant erythropoietic protoporphyria by a low expression of the normal ferrochelatase allele.Am J Hum Genet. 1996; 58: 292-299PubMed Google Scholar, Gouya et al., 1999Gouya L Puy H Lamoril J Da Silva V Grandchamp B Nordmann Y Deybach JC Inheritance in erythropoietic protoporphyria: a common wild-type ferrochelatase allelic variant with low expression accounts for clinical manifestation.Blood. 1999; 93: 2105-2110PubMed Google Scholar, Gouya et al., 2002Gouya L Puy H Robreau AM Bourgeois M Lamoril J Da Silva V Grandchamp B Deybach JC The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH.Nat Genet. 2002; 30: 27-28Crossref PubMed Scopus (219) Google Scholar), and 88 new cases were investigated. The 88 new patients were subjected to the direct sequencing of all coding regions, the intron/exon junctions, the 1.3-kb upstream promoter region, and the two polyadenylation signal regions. In 18 overt patients (15.9%), we were not able to identify any FECH gene defect, even though the clinical manifestations, the erythrocyte protoporphyrin level, and the FECH enzyme activity closely matched EPP. The possibility that the entire gene had been deleted was excluded by the evidence that they were heterozygous for at least two intragenic SNPs. Of the 95 patients in whom gene defects were identified, 90 were heterozygous for a FECH mutation and 5 displayed compound heterozygosity. Twenty-seven previously unreported mutations were identified (fig. 1A and table 1). These were highly heterogeneous and usually family specific. The predominant type of mutations were missense mutations in the coding regions (36.4%), followed by intronic mutations predicting anomalous RNA splicing (24.2%), small deletions and insertions (21.2%), and nonsense mutations (15.2%). Most of the mutations produced null alleles. This distribution is similar to previously published EPP mutation patterns (Rüfenacht et al. Rüfenacht et al., 1998Rüfenacht UB Gouya L Schneider-Yin X Puy H Schafer BW Aquaron R Nordmann Y Minder EI Deybach JC Systematic analysis of molecular defects in the ferrochelatase gene from patients with erythropoietic protoporphyria.Am J Hum Genet. 1998; 62: 1341-1352Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar; Schneider-Yin et al. Schneider-Yin et al., 2000Schneider-Yin X Gouya L Meier-Weinand A Deybach JC Minder EI New insights into the pathogenesis of erythropoietic protoporphyria and their impact on patient care.Eur J Pediatr. 2000; 159: 719-725Crossref PubMed Scopus (57) Google Scholar).Table 1EPP Patients with Compound Heterozygotism for Two Rare FECH AllelesPatientFECH ActivityaIn nanomoles of mesozinc/hour/milligram of protein at 37 °C, measured in peripheral lymphocytes (normal value [mean ± SD] = 4.83 ± 0.91).Erythrocyte ProtoporphyrinbIn nanomoles/liter (N<1,900).Allele 1Allele 2P10.250,000S222G, IVS" @default.
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• W2093804948 date "2006-01-01" @default.
• W2093804948 modified "2023-10-18" @default.
• W2093804948 title "Contribution of a Common Single-Nucleotide Polymorphism to the Genetic Predisposition for Erythropoietic Protoporphyria" @default.
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