A novel mutation in the ferrochelatase gene associated with erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP) is a hereditary disorder caused by mutations of the ferrochelatase gene. We investigated a Japanese patient with a dominant form of erythropoietic protoporphyria for a ferrochelatase mutation. Sequence analysis of the proband's ferrochelatase cDNA revealed a T to C point mutation at nucleotide 557. This mutation resulted in the replacement of Ile by Thr at amino acid position 186, a novel mutation in erythropoietic protoporphyria. An increase in ferrochelatase activity was not observed in the crude extract of E. coli over-expressing the mutant protein compared with the control, whereas a marked increase in activity was observed in that over-expressing the wild type. Prediction of the secondary structure of ferrochelatase suggested that the Ile186-->Thr mutation changed the original beta-sheet structure to an alpha helix in the region including amino acid residue of mutation. We conclude that, in the patient, the Ile186-->Thr mutation had abolished enzyme activity, possibly by disrupting the secondary structure, thereby causing erythropoietic protoporphyria.