title: Novel null-allele mutations and genotype-phenotype correlation in Argentinean patients with erythropoietic protoporphyria.
abstract: Erythropoietic protoporphyria (EPP) is an inherited disorder of porphyrin metabolism in which decreased activity of ferrochelatase (FECH) leads to accumulation of protoporphyrin IX (PP IX) in red blood cells, plasma, liver, and bile, and increased PP IX excretion in feces. Clinically, EPP is characterized by photosensitivity that begins in early childhood and includes burning, swelling, itching, and painful erythema in sun-exposed areas. Chronic liver disease is an important complication in a minority of EPP patients, and in some cases liver transplantation has been performed. So far, about 110 different mutations and several polymorphisms have been characterized in the human FECH gene. The relationship between mutations, polymorphisms, and porphyria development in Argentinean patients was investigated. This is the first genetic study carried out in the Argentinean population. In five Argentinean EPP families we detected three novel mutations: a deletion (451delT) producing a stop codon located 18 codons downstream from the mutation and two splicing mutations: IVS1-2A>G leading to exon 2 skipping and IVS4-2A>G, which causes the loss of the first 48 bp of exon 5. We also found two previously described mutations: C343T and 400delA, which produce stop codons. All patients had an FECH activity 25% of normal and also had the polymorphisms -251A>G in the promoter region and IVS1-23 C>T and IVS3-48 T>C. Our findings provide supporting evidence for the concept that the inheritance of the low expression allele IVS3-48C in trans with a mutation in the FECH gene is necessary for EPP to become clinically manifest.
authors.affiliation: Laboratory of Metabolic Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Parera
authors.forename: Rita H
authors.initials: RH
authors.lastname: Koole
authors.forename: Gardi
authors.initials: G
authors.lastname: Minderman
authors.forename: Annie
authors.initials: A
authors.lastname: Edixhoven
authors.forename: Maria V
authors.initials: MV
authors.lastname: Rossetti
authors.forename: Alcira
authors.initials: A
authors.lastname: Batlle
authors.forename: Felix W M
authors.initials: FW
authors.lastname: de Rooij
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001118:Argentina; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods*; D005190:Family; D005260:Female; D005294:Ferrochelatase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D046351:Protoporphyria, Erythropoietic / Q000235:genetics*
chemical_list: D005294:Ferrochelatase
references.citation: Lancet. 1961 Aug 26;2(7200):448-51
references.pmid: 13765301
references.citation: Blood. 1999 Mar 15;93(6):2105-10
references.pmid: 10068685
references.citation: Hum Genet. 2004 Feb;114(3):256-62
references.pmid: 14669009
references.citation: Arch Dermatol. 2007 Sep;143(9):1125-9
references.pmid: 17875872
references.citation: J Hum Genet. 2003;48(2):70-6
references.pmid: 12601550
references.citation: J Invest Dermatol. 1996 Feb;106(2):346-50
references.pmid: 8601739
references.citation: Liver Transpl. 2005 Dec;11(12):1590-6
references.pmid: 16315313
references.citation: J Med Genet. 2004 Aug;41(8):e105
references.pmid: 15286165
references.citation: J Invest Dermatol. 1998 Sep;111(3):406-9
references.pmid: 9740232
references.citation: Genomics. 1991 Dec;11(4):1152-4
references.pmid: 1783383
references.citation: J Hepatol. 2008 Feb;48(2):375-9
references.pmid: 18160121
references.citation: J Invest Dermatol. 2001 Dec;117(6):1521-5
references.pmid: 11886517
references.citation: Cell Mol Biol (Noisy-le-grand). 2002 Feb;48(1):91-6
references.pmid: 11929053
references.citation: Mol Genet Metab. 2003 Sep-Oct;80(1-2):196-206
references.pmid: 14567969
references.citation: Clin Chem. 1988 Dec;34(12):2481-5
references.pmid: 3197287
references.citation: Clin Chem. 1986 Dec;32(12):2137-42
references.pmid: 3779978
references.citation: Br J Dermatol. 2008 Jul;159(1):182-91
references.pmid: 18460026
references.citation: Am J Hum Genet. 1996 Feb;58(2):292-9
references.pmid: 8571955
references.citation: Nat Genet. 2002 Jan;30(1):27-8
references.pmid: 11753383
references.citation: Am J Hum Genet. 1992 Jun;50(6):1203-10
references.pmid: 1376018
references.citation: Hum Genet. 1986 Aug;73(4):320-6
references.pmid: 3017841
references.citation: Am J Hum Genet. 1998 Jun;62(6):1341-52
references.pmid: 9585598
references.citation: Biochem Biophys Res Commun. 1990 Dec 14;173(2):748-55
references.pmid: 2260980
references.citation: Biomed Chromatogr. 1987;2(4):164-8
references.pmid: 3507230
references.citation: J Invest Dermatol. 1997 Nov;109(5):688-91
references.pmid: 9347801
references.citation: Clin Chem. 2001 Jun;47(6):1112-3
references.pmid: 11375302
references.citation: Mol Genet Metab. 2007 Apr;90(4):402-7
references.pmid: 17196862
references.citation: Biochem Biophys Res Commun. 1991 Dec 16;181(2):594-9
references.pmid: 1755842
references.citation: Eur J Biochem. 1992 Apr 1;205(1):217-22
references.pmid: 1555582