Mutations in the iron-sulfur cluster ligands of the human ferrochelatase lead to erythropoietic protoporphyria

Ferrochelatase (FECH; EC 4.99.1.1) catalyzes the terminal step of the heme biosynthetic pathway. Defects in the human FECH gene may lead to erythropoi etic protoporphyria (EPP), a rare inherited disorder characterized by dimin ished FECH activity with protoporphyrin overproduction and subsequent skin photosensitivity and in rare cases liver failure. Inheritance of EPP appear ed to be autosomal dominant with possible modulation by low expression of t he wild-type FECH allele, Animal FECHs have been demonstrated to be [2Fe-2S ] cluster-containing proteins. Although enzymatic activity and stability of the protein appear to be dependent on the presence of the [2Fe-2S] cluster , the physiologic role of the iron-sulfur center remains to be unequivocall y established. Three of the 4 [2Fe-2S] cluster-coordinating cysteines (ie, C403, C406, and C411 in the human enzyme) are located within the C-terminal domain. In this study 5 new mutations are identified in patients with EPP. Three of the point mutations, in 3 patients, resulted in FECH variants wit h 2 of the [2Fe-2S] cluster cysteines substituted with tyrosine, serine, an d glycine (ie, C406Y, C406S, and C411G) and with undetectable enzymatic act ivity. Further, one of the patients exhibited a triple point mutation (T-12 24-->A, C-1225-->T, and T-1231-->G) leading to the N408K/P409S/C411G varian t. This finding is entirely novel and has not been reported in EPP. The mut ations of the codons for 2 of, the [2Fe-2S] cluster ligands in patients wit h EPP supports the importance of the iron-sulfur center for the proper func tioning of mammalian FECH and, in at least humans, its absence has a direct clinical impact. (Blood, 2000;96:1545-1549) (C) 2000 by The American Socie ty of Hematology.