title: Mutations in the iron-sulfur cluster ligands of the human ferrochelatase lead to erythropoietic protoporphyria.
abstract: 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 erythropoietic protoporphyria (EPP), a rare inherited disorder characterized by diminished FECH activity with protoporphyrin overproduction and subsequent skin photosensitivity and in rare cases liver failure. Inheritance of EPP appeared to be autosomal dominant with possible modulation by low expression of the 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 unequivocally 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 with 2 of the [2Fe-2S] cluster cysteines substituted with tyrosine, serine, and glycine (ie, C406Y, C406S, and C411G) and with undetectable enzymatic activity. Further, one of the patients exhibited a triple point mutation (T(1224)-->A, C(1225)-->T, and T(1231)-->G) leading to the N408K/P409S/C411G variant. This finding is entirely novel and has not been reported in EPP. The mutations of the codons for 2 of the [2Fe-2S] cluster ligands in patients with EPP supports the importance of the iron-sulfur center for the proper functioning of mammalian FECH and, in at least humans, its absence has a direct clinical impact. (Blood. 2000;96:1545-1549)
authors.affiliation: Zentrallabor, Stadtspital Triemli, Zürich, Switzerland.
authors.forename: X
authors.initials: X
authors.lastname: Schneider-Yin
authors.forename: L
authors.initials: L
authors.lastname: Gouya
authors.forename: M
authors.initials: M
authors.lastname: Dorsey
authors.forename: U
authors.initials: U
authors.lastname: Rüfenacht
authors.forename: J C
authors.initials: JC
authors.lastname: Deybach
authors.forename: G C
authors.initials: GC
authors.lastname: Ferreira
mesh_terms: D005260:Female; D005294:Ferrochelatase / Q000235:genetics*; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000235:genetics*; D008024:Ligands; D008297:Male; D005810:Multigene Family; D009154:Mutation; D010375:Pedigree; D017121:Porphyria, Hepatoerythropoietic / Q000209:etiology* / Q000235:genetics*
chemical_list: D007506:Iron-Sulfur Proteins; D008024:Ligands; D005294:Ferrochelatase