Artículo

Colombo, F.P.; Rossetti, M.V.; Méndez, M.; Martínez, J.E.; Enríquez De Salamanca, R.; Del C. Batlle, A.M.; Parera, V.E. "Functional associations of genetic variants involved in the clinical manifestation of erythropoietic protoporphyria in the Argentinean population" (2013) Journal of the European Academy of Dermatology and Venereology. 27(6):754-762
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Abstract:

Background Combined inheritance of genetic variants in ferrochelatase gene (FECH) are implicated in clinical manifestation of Erythropoietic Protoporphyria (EPP). Objective Identify the genetic variants in FECH gene and their associations in the expression of EPP in Argentina. Determine the allelic frequency of polymorphic variants, associations in cis and its linkage disequilibrium. Methods The FECH gene was PCR-amplified and sequenced. Allelic variants of intragenic polymorphisms were identified by PCR followed by sequencing or restriction digestion analysis. Residual FECH activity was determined by prokaryotic expression in Escherichia coli JM109. Data were analyzed using Haploview and Statistix 9. Results Ten mutations were identified: three novel (p.S222N; p.R298X and p.R367X) and seven already known (g.12490-18067del; p.R115X; p.I186T; c.580-584delTACAG; c.598 + 1 G>T; p.Y209X and p.W310X). The p.R115X mutation was found in two families. The p.S222N mutation expressed 5% of normal activity. Only individuals who inherited a mutation combined in trans to a low expression allele c.1-251G, c.68-23T, and c.315-48C, showed clinical symptoms. The absence of c.315-48C variant was sufficient for not triggering EPP. However, these variants showed high levels of cosegregation and GTC haplotype is over-represented in EPP patients. Conclusion In the dominant inheritance form of EPP, c.315-48C variant in trans to the mutated allele is sufficient to trigger the disease. The presence of GTC haplotype in all patients with dominant EPP could be due to the high level of cosegregation of c.315-48C with c.1-251G and c.68-23T variants in our population. © 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology.

Registro:

Documento: Artículo
Título:Functional associations of genetic variants involved in the clinical manifestation of erythropoietic protoporphyria in the Argentinean population
Autor:Colombo, F.P.; Rossetti, M.V.; Méndez, M.; Martínez, J.E.; Enríquez De Salamanca, R.; Del C. Batlle, A.M.; Parera, V.E.
Filiación:Centro de Investigaciones Sobre Porfirinas y Porfirias (CIPYP) -CONICET, Hospital de Clínicas josé de San Martín-UBA, Av. Cõrdoba 2351, 1 subsuelo, Buenos Aires, (1120), Argentina
Departamento de Química Biolõgica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Centro de Investigaciõn, Hospital 12 de Octubre, Universidad Complutense de Madrid, Av. de Cõrdoba s/n, (28041), Madrid, Spain
Palabras clave:ferrochelatase; adolescent; adult; Argentina; article; child; clinical feature; erythropoietic protoporphyria; gene expression; gene frequency; gene linkage disequilibrium; gene mutation; genetic association; genetic variability; haplotype; human; preschool child; priority journal; school child; Adolescent; Adult; Argentina; Child; Child, Preschool; Ferrochelatase; Genetic Variation; Humans; Middle Aged; Mutation; Polymorphism, Genetic; Protoporphyria, Erythropoietic; Young Adult
Año:2013
Volumen:27
Número:6
Página de inicio:754
Página de fin:762
DOI: http://dx.doi.org/10.1111/j.1468-3083.2012.04566.x
Título revista:Journal of the European Academy of Dermatology and Venereology
Título revista abreviado:J. Eur. Acad. Dermatol. Venereol.
ISSN:09269959
CODEN:JEAVE
CAS:ferrochelatase, 9012-93-5; Ferrochelatase, 4.99.1.1
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09269959_v27_n6_p754_Colombo

Referencias:

  • Magnus, I.A., Jarrett, A., Prankerd, T.A., Rimington, C., Erythropoietic protoporphyria. A new porphyria syndrome with solar urticaria due to protoporphyrinaemia (1961) Lancet, 2, pp. 448-451
  • Nakahashi, Y., Taketani, S., Okuda, M., Molecular cloning and sequence analysis of cDNA encoding human ferrochelatase (1990) Biochem Biophys Res Commun, 173, pp. 748-755
  • Whitcombe, D.M., Carter, N.P., Albertson, D.G., Assignment of human ferrochelatase gene (FECH) and a locus for protoporphyria on chromosome 18q22 (1991) Genomics, 11, pp. 1152-1154
  • Taketani, S., Inazawa, J., Nakahashi, Y., Structure of human ferrochelatase gene. Exon/intron gene organization and location of the gene to chromosome 18 (1992) Eur J Biochem, 205, pp. 217-222
  • Brenner, D.A., Didier, J.M., Frasier, F., A molecular defect in human protoporphyria (1992) Am J Hum Genet, 50, pp. 1203-1210
  • Dailey, H.A., Dailey, T.A., Wu, C.K., Ferrochelatase at the millennium: Structures, mechanisms and [2Fe-2S] clusters (2000) Cell Mol Life Sci, 57, pp. 1909-1926
  • Wu, C.K., Dailey, H.A., Rose, J.P., The 2.0 Å structure of human ferrochelatase, the terminal enzyme of heme biosynthesis (2001) Nat Struct Biol, 8, pp. 156-160
  • Bonkowsky, H.L., Bloomer, J.R., Ebert, P.S., Mahoney, M.J., Heme synthetase deficiency in human protoporphyria. Demonstration of the defect in liver and cultured skin fibroblasts (1975) J Clin Invest, 56, pp. 1139-1148
  • Bottomley, S.S., Tanaka, M., Everett, M.A., Diminished erythroid ferrochelatase activity in protoporphyria (1975) J Lab Clin Med, 86, pp. 126-131
  • Morton, K.O., Schneider, F., Weimer, M.K., Hepatic and bile porphyrins in patients with protoporphyria and liver failure (1988) Gastroenterology, 94, pp. 1488-1492
  • Kappas, A., Sassa, S., Gallbraith, R.A., Nordmann, Y., The porphyrias (1989) The Metabolic Basis of Inherited Disease, pp. 1301-1384. , In Scriver C.R. Beaudet A.L. Sly W.S. Valle D. eds. 6th edn. McGraw-Hill, New York
  • Anderson, K.E., Sassa, S., Bishop, D.F., Desnick, R.J., The porphyrias (2001) The Metabolic and Molecular Bases of Inherited Disease, pp. 2961-3062. , In Scriver C.R. Beaudet A.L. Sly W.S. Valle D. eds. 8th edn. McGraw Hill, New York
  • Lehmann, P., Scharffetter, K., Kind, P., Goerz, G., Erythopoietic protoporphyria: Synopsis of 20 patients (1991) Hautarzt, 42, pp. 570-574
  • Doss, M.O., Frank, M., Hepatobiliary implications and complications in protoporphyria, a 20-year study (1989) Clin Biochem, 22, pp. 223-229
  • McGuire, B.M., Bonkovsky, H.L., Carithers, Jr.R.L., Liver transplantation for erythropoietic protoporphyria liver disease (2005) Liver Transpl, 11, pp. 1590-1596
  • Went, L.N., Klasen, E.C., Genetic aspects of erythropoietic protoporphyria (1984) Ann Hum Genet, 48, pp. 105-117
  • Gouya, L., Deybach, J.C., Lamoril, J., Modulation of the phenotype in dominant erythropoietic protoporphyria by a low expression of the normal ferroquelatase allele (1996) Am J Hum Genet, 58, pp. 292-299
  • Gouya, L., Puy, H., Lamoril, J., Inheritance in erythropoietic protoporphyria: A common Wild-Type ferrochelatase allelic variant with low expression accounts for Clinical Manifestation (1999) Blood, 93, pp. 2105-2110
  • Gouya, L., Puy, H., Robreau, A.M., The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH (2002) Nat Genet, 30, pp. 27-28
  • Di Pierro, E., Brancaleoni, V., Moriondo, V., Co-existence of two functional mutations on the same allele of the human ferrochelatase gene in erythropoietic protoporphyria (2007) Clin Genet, 71, pp. 84-88
  • Lamoril, J., Boulechfar, S., Verneuil, H., Grandchamp, B., Nordmann, Y., Deybach, J.C., Human erythropoietic protoporphyria: Two point mutation in the ferrochelatase gene (1991) Biochem Biophys Res Commun, 181, pp. 594-599
  • Sarkany, R.P.E., Alexander, G., Cox, T.M., Recessive inheritance of erythropoietic protoporphyria with liver failure (1994) Lancet, 343, pp. 1394-1396
  • Parera, V.E., Minderman, G., Koole, R., Protoporfiria Eritropoyética (2000) Cinco Nuevas Mutaciones en El Gen de la Ferroquelatasa Medicina, 60, p. 842
  • Poh-Fitzpatrick, M.B., Wang, X., Anderson, K.E., Bloomer, J.R., Bolwell, B., Lichtin, A.E., Erythropoietic protoporphyria: Altered phenotype after bone marrow transplantation for myelogenous leukemia in a patient heteroallelic for ferrochelatase gene mutations (2002) J Am Acad Dermatol, 46, pp. 861-866
  • Whatley, S.D., Mason, N.G., Khan, M., Autosomal recessive erythropoietic protoporphyria in the United Kingdom: Prevalence and relationship to liver disease (2004) J Med Genet, 41, pp. e105
  • Gouya, L., Martin-Schmitt, C., Robreau, A.M., Contribution of a common single nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria (2006) Am J Hum Genet, 78, pp. 2-14
  • Herrero, C., To-Figueras, J., Badenas, C., Clinical, biochemical, and genetic study of 11 patients with erythropoietic protoporphyria including one with homozygous disease (2007) Arch Dermatol, 143, pp. 1125-1129
  • Holme, S.A., Whatley, S.D., Roberts, A.G., Seasonal palmar keratoderma in erythropoietic protoporphyria indicates autosomal recessive inheritance (2009) J Invest Dermatol, 129, pp. 599-605
  • Méndez, M., Poblete-Gutiérrez, P., Morán-Jiménez, M.J., A homozygous mutation in the ferrochelatase gene underlies erythropoietic protoporphyria associated with palmar keratoderma (2009) Br J Dermatol, 160, pp. 1330-1334
  • Minder, E.I., Schneider-Yin, X., Mamet, R., A homoallelic FECH mutation in a patient with both erythropoietic protoporphyria and palmar keratoderma (2010) J Eur Acad Dermatol Venereol, 24, pp. 1349-1353
  • Whatley, S.D., Mason, N.G., Holme, S.A., Molecular epidemiology of erythropoietic protoporphyria in the U.K (2010) Br J Dermatol, 162, pp. 642-646
  • Wahlin, S., Floderus, Y., Stål, P., Harper, P., Erythropoietic protoporphyria in Sweden: Demographic, clinical, biochemical and genetic characteristics (2011) J Intern Med, 269, pp. 278-288
  • Rufenacht, U.B., Gouya, L., Schneider-Yin, X., Systematic Analysis of Molecular Defects in the Ferrochelatase Gene from Patients with Erythropoietic Protoporphyria (1998) Am J Hum Genet, 62, pp. 1341-1352
  • Saruwatari, H., Ueki, Y., Yotsumoto, S., Genetic analysis of the ferrochelatase gene in eight Japonese patients from seven families with erythopoietic protoporphyria (2006) J Dermatol, 33, pp. 603-608
  • Aurizi, C., Schneider-Yin, X., Sorge, F., Heterogeneity of mutations in the ferrochelatase gene in Italian patients with erythropoietic protoporphyria (2007) Mol Genet Metab, 90, pp. 402-407
  • Whatley, S.D., Mason, N.G., Holme, S.A., Gene dosage analysis identifies large deletions of the FECH gene in 10% of families with erythropoietic protoporphyria (2007) J Invest Dermatol, 127, pp. 2790-2794
  • Zhou, S.N., Xiao, S.X., Peng, Z.H., A novel mutation of the FECH gene in a Chinese family with erythropoietic protoporphyria (2007) J Dermatol Sci, 48, pp. 145-147
  • Parker, M., Corrigall, A.V., Hift, R.J., Meissner, P.N., Molecular characterization of Erythropoietic protoporphyria in South Africa (2008) Br J Dermatol, 159, pp. 182-191
  • Di Pierro, E., Brancaleoni, V., Besana, V., A 10376 bp deletion of FECH gene responsible for erythropoietic protoporphyria (2008) Blood Cells Mol Dis, 40, pp. 233-236
  • Brancaleoni, V., Di Pierro, E., Besana, V., Gene Symbol: FECH. Disease: Porphyria, erythropoietic (2008) Hum Genet, 124, pp. 293-324
  • Schneider-Yin, X., Mamet, R., Minder, E.I., Schoenfeld, N., Biochemical and molecular diagnosis of erythropoietic protoporphyria in an Ashkenazi Jewish family (2008) J Inherit Metab Dis, 31, pp. S363-S367
  • Parera, V.E., Koole, R.H., Minderman, G., Novel null-allele mutations and genotype-phenotype correlation in Argentinean patients with erythropoietic protoporphyria (2009) Mol Med, 15, pp. 425-431
  • Lau, K.C., Lam, C.W., Fong, B., DNA-based diagnosis of erythropoietic protoporphyria in two families and the frequency of a low-expression FECH allele in a Chinese population (2009) Clin Chim Acta, 400, pp. 132-134
  • Li, C., Di Pierro, E., Brancaleoni, V., A novel large deletion and three polymorphisms in the FECH gene associated with erythropoietic protoporphyria (2009) Clin Chem Lab Med, 47, pp. 44-46
  • Ma, J., Xiao, S., An, J., A novel splicing mutation and haplotype analysis of the FECH gene in a Chinese family with erythropoietic protoporphyria (2010) J Eur Acad Dermatol Venereol, 6, pp. 726-729
  • Human Gene Mutation Database, , http://www.hgmd.cf.ac.uk/ac/gene.php?gene=FECH, The Institute of Medical genetics in Cardiff. Available at Accessed February 18, 2012
  • Kitts, A., Sherry, S., NCBI Handbook the Single Nucleotide Polymorphism Database (DbSNP) of Nucleotide Sequence Variation, , http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?chooseRs=all&go= Go&locusId=2235, Available at Accessed February 18, 2012
  • Caceres, J.F., Kornblihtt, A.R., Alternative splicing: Multiple control mechanisms and involvement in human disease (2002) Trends Genet, 18, pp. 186-193
  • Nakahashi, Y., Fujita, H., Taketani, S., The molecular defect of ferrochelatase in a patient with erythropoietic protoporphyria (1992) Proc Natl Acad Sci USA, 89, pp. 281-285
  • Di Pierro, E., Cappellini, M.D., Mazzucchelli, R., A point mutation affecting an SP1 binding site in the promoter of the ferrochelatase gene impairs gene transcription and causes erythropoietic protoporphyria (2005) Exp Hematol, 33, pp. 584-591
  • Magness, S.T., Tugores, A., Brenner, D.A., Analysis of ferrochelatase expression during hematopoietic development of embryonic stem cells (2000) Blood, 95, pp. 3568-3577
  • Batlle, A.M.C., El Laboratorio de las Porfirias (1997) Acta Bioquímica Clínica Latinoamericana, pp. 141-175. , Porfirias y Porfirinas , eds. Aspectos clínicos, bioquímicos y biología molecular. Actualizaciones Médico-Bioquímicas. Federaciõn Bioquímica de la Provincia de Buenos Aires, Argentina
  • Wiman, A., Floderus, Y., Harper, P., Novel mutations and phenotypic effect of the splice site modulator IVS3-48C in nine Swedish families with erythropoietic protoporphyria (2003) J Hum Genet, 48, pp. 70-76
  • Henriksson, M., Timonen, K., Mustajoki, P., Four novel mutations in the ferrochelatase gene among erythropoietic protoporphyria patients (1996) J Invest Dermatol, 106, pp. 346-350
  • Gouya, L., Schneider-Yin, X., Rüfenacht, U., Mutations in the ferrochelatase gene of four Spanish patients with erythropoietic protoporphyria (1998) J Invest Dermatol, 111, pp. 406-409
  • Kong, X.F., Ye, J., Gao, D.Y., Identification of a ferrochelatase mutation in a Chinese family with erythropoietic protoporphyria (2008) J Hepatol, 48, pp. 375-379
  • Hartmann, L., Theiss, S., Niederacher, D., Schaal, H., Diagnostics of pathogenic splicing mutations: Does bioinformatics cover all bases? (2008) Front Biosci, 13, pp. 3252-3272
  • Lecha, M., Puy, H., Deybach, J.C., Erythropoietic protoporphyria (2009) Orphanet J Rare Dis, 4, p. 19
  • Whatley, S.D., Ducamp, S., Gouya, L., C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload (2008) Am J Hum Genet, 83, pp. 408-414
  • Imoto, S., Tanizawa, Y., Sato, Y., A novel mutation in the ferrochelatase gene associated with erytropoietic protoporphyria (1996) Br J Haematol, 94, pp. 191-197
  • Schneider-Yin, X., Schafer, B.W., Tonz, O., Minder, E.I., Human ferrochelatase: A novel mutation in patients with erythropoietic protoporphyria and an isoform caused by alternative splicing (1995) Hum Genet, 95, pp. 391-396
  • Frank, J., Nelson, J., Wang, X., Erythropoietic protoporphyria: Identification of novel mutations in the ferrochelatase gene and comparison of biochemical markers versus molecular analysis as diagnostic strategies (1999) J Investig Med, 47, pp. 278-284
  • Di Pierro, E., Moriondo, V., Cappellini, M.D., Gene Symbol: FECH. Disease: Porphyria, erythropoietic (2004) Hum Genet, 114, p. 221

Citas:

---------- APA ----------
Colombo, F.P., Rossetti, M.V., Méndez, M., Martínez, J.E., Enríquez De Salamanca, R., Del C. Batlle, A.M. & Parera, V.E. (2013) . Functional associations of genetic variants involved in the clinical manifestation of erythropoietic protoporphyria in the Argentinean population. Journal of the European Academy of Dermatology and Venereology, 27(6), 754-762.
http://dx.doi.org/10.1111/j.1468-3083.2012.04566.x
---------- CHICAGO ----------
Colombo, F.P., Rossetti, M.V., Méndez, M., Martínez, J.E., Enríquez De Salamanca, R., Del C. Batlle, A.M., et al. "Functional associations of genetic variants involved in the clinical manifestation of erythropoietic protoporphyria in the Argentinean population" . Journal of the European Academy of Dermatology and Venereology 27, no. 6 (2013) : 754-762.
http://dx.doi.org/10.1111/j.1468-3083.2012.04566.x
---------- MLA ----------
Colombo, F.P., Rossetti, M.V., Méndez, M., Martínez, J.E., Enríquez De Salamanca, R., Del C. Batlle, A.M., et al. "Functional associations of genetic variants involved in the clinical manifestation of erythropoietic protoporphyria in the Argentinean population" . Journal of the European Academy of Dermatology and Venereology, vol. 27, no. 6, 2013, pp. 754-762.
http://dx.doi.org/10.1111/j.1468-3083.2012.04566.x
---------- VANCOUVER ----------
Colombo, F.P., Rossetti, M.V., Méndez, M., Martínez, J.E., Enríquez De Salamanca, R., Del C. Batlle, A.M., et al. Functional associations of genetic variants involved in the clinical manifestation of erythropoietic protoporphyria in the Argentinean population. J. Eur. Acad. Dermatol. Venereol. 2013;27(6):754-762.
http://dx.doi.org/10.1111/j.1468-3083.2012.04566.x