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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1545-1549
RED CELLS
Mutations in the iron-sulfur cluster ligands of the human
ferrochelatase lead to erythropoietic protoporphyria
Xiaoye Schneider-Yin,
Laurent Gouya,
Morna Dorsey,
Urszula Rüfenacht,
Jean-Charles Deybach, and
Glória C. Ferreira
From the Zentrallabor, Stadtspital Triemli,
Zürich, Switzerland; Centre Français des
Porphyries, INSERM U409, Faculté X. Bichat, Hôpital Louis
Mourier, Colombes, France; Department of Biochemistry and
Molecular Biology, College of Medicine, Institute for Biomolecular
Science, and H. Lee Moffitt Cancer Center and Research Institute,
University of South Florida, Tampa, FL.
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 (T1224 A, C1225T, and
T1231G) 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.
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