Co-existence of two functional mutations on the same allele of the human ferrochelatase gene in erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP) is an autosomal dominant disease with incomplete penetrance due to reduced activity of ferrochelatase (FECH), a mitochondrial enzyme that catalyzes the final step of the heme biosynthetic pathway. The clinical phenotype of EPP results from co-inheritance of a mutated allele and a wild-type low-expressed allele of the FECH gene. To date, more than 88 different mutations have been identified in the FECH gene of patients with EPP. There are evidences suggesting that an entire haplotype (-251G, IVS1-23T and IVS3-48C) reduces allele expression. In this study, we searched for the -251A/G, IVS1-23C/T and IVS3-48T/C polymorphisms in two unrelated Italian families with EPP. In all the patients, carrying the -250G>C mutation in the promoter region, the IVS3-48C on the other allele showed apparent homozygosity and absence of Mendelian segregation. By RNA and long polymerase chain reaction analysis, we identified a deletion of 5576 bp (g12490_18067), including exons 3 and 4, in cis with the -250G>C mutation in the promoter.