Erythropoietic protoporphyria (EPP) is an autosomal dominant disease with incomplete penetrance, due to reduced activity of ferrochelatase (FECH), a mitochondrial enzyme that catalyzes the insertion of iron in the protoporphyrin molecule in the final step of the heme biosynthetic pathway. The disease is biochemically characterized by increased protoporphyrins in erythrocytes, plasma and faeces and normal levels in urine. The clinical manifestations have a childhood onset, characterized by mild to moderate cutaneous photosensitivity, mild anemia and, in 5–10% of the cases, by progressive hepatic failure. Diagnosis of EPP can be supported by the simple measurement with flow citometry of fluorescent erythrocytes in peripheral blood. The phenotype of EPP results from coinheritance of a mutated allele and a wild-type low expressed allele of the FECH gene that spans about 45 kb on the long arm of chromosome 18. The FECH gene encodes for a precursor of 423 amino acid residues that is targeted to the matrix side of the inner mitochondrial membrane via a 62 amino acid cleavable leader sequence. A single promoter directs both housekeeping and erythroid expression, but two polyadenylation sites produce two mRNAs of different length. The molecular analysis of FECH gene has allowed the identification of more than 100 different mutations responsible for EPP, showing a high genetic heterogeneity. Aim of this study was to search for molecular abnormalities in four patients with clinical and biochemical signs of EPP. Molecular analysis was performed by PCR and direct sequencing of the promoter, the entire coding region and the splicing junctions of the gene. In patients who remained negative for mutations, DNA analysis was completed by long-PCR and chromosome walking. In this study four different molecular defects have been identified: two missense mutations and two large deletions in the first region of gene. One A>G substitution at nucleotide 362 in exon 4 resulting in a Glu to Gly amino acid substitution at position 121; one change C>T in position 782 of exon 7 causing a Ser 261Phe substitution; the c.1-7887_67+2422del10376bp and the c.1-9628_67+2871del12566bp. Even though with different breakpoints, both deletions include a portion of upstream intergenic region, the promoter, the exon 1 and a portion of intron 1 of the FECH gene preventing the expression of the mutated allele. This deletions are probably caused by unequal intragenic recombination between ALU sequences which have been found close to the breakpoints. Recently others deletions involving ALU sequences were described suggesting that large deletions can affect the FECH gene and cause of EPP.

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