Wided Najahi-Missaoui and Harry A. Dailey

Biomedical and Health Sciences Institute, and Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia, USA 30602

Mutations resulting in diminished activity of the dimeric enzyme ferrochelatase are a prerequisite for the inherited disorder erythropoietic protoporphyria (EPP).  Patients with clinical EPP have only 10-30% of normal levels of ferrochelatase activity and while many EPP patients possess one mutant allele and one “low expression” normal allele, the possibility remains that for some, low ferrochelatase activity may result from an EPP mutation that has an impact on both subunits of the wild-type/mutant heterodimer.  Herein we present data for twelve ferrochelatase wild-type/EPP mutant heterodimers showing that some mutations result in heterodimers with the residual activity anticipated from individual constituents, but other heterodimers had significantly lower activity than would have been predicted.  While the data do not allow an a priori prediction of heterodimeric residual activity based solely upon in vitro activity of EPP homodimers or position of the mutated residue within ferrochelatase, mutations that affect the dimer interface or [2Fe-2S] cluster have a significantly greater impact on residual activity than would be predicted.  These data suggest that some EPP mutations may result in clinically overt EPP in the absence of a low expression wild-type allele and this is of potential significance for genetic counseling of EPP patients.