Novel null–allele mutations and genotype-phenotype correlation in argentinean patients with erythropoietic protoporphyria.

PARERA VE; KOOLE RH; MINDERMAN G; EIDIXHOVEN A; ROSSETTI MV; BATLLE A; DE ROOIJ FWM

MOLECULAR MEDICINE

Feinstein Institute

Año: 2009 vol. 15 p. 425 - 431

1076-1551

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, bile and  increased excretion in  feces. Clinically, EPP is characterized by photosensitivity that includes burning, swelling, itching and painful erythema in sun exposed areas from early childhood. 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 3 novel mutations: a deletion (451delT) producing a stop codon 18 codons downstream from the mutation and 2 splicing mutations: IVS1-2A>G leading to exon 2 skipping and IVS4-2A>G which causes the loss of the first 48bp of exon 5. We have also found 2 previously described mutations: C343T and 400delA  producing stop codons. All patients had a FECH activity 25% of normal and also had the polymorphisms -251A>G in the promoter region, 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.