Human Molecular Genetics Advance Access originally published online on April 2, 2007
Human Molecular Genetics 2007 16(10):1241-1252; doi:10.1093/hmg/ddm072
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Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy
1 Department of Molecular Neurogenetics, 2 Department of Child Neurology, 3 Department of Neuroradiology, Foundation IRCCS Neurological Institute ‘C. Besta’, Milano, Italy, 4 Department of Genetics, Biology of Microrganisms, Anthropology and Evolution, University of Parma, Parma, Italy and 5 Department of Pediatrics, Meyer Children's Hospital, Firenze, Italy
* To whom correspondence should be addressed at: Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute ‘C. Besta’, via Libero Temolo 4, 20126 Milano, Italy. Tel: +39 0223942630; Fax: +39 0223942619; Email: zeviani{at}istituto-besta.it
Received February 6, 2007; Revised February 25, 2007; Accepted March 16, 2007
We investigated two unrelated children with an isolated defect of mitochondrial complex III activity. The clinical picture was characterized by a progressive encephalopathy featuring early-onset developmental delay, spasticity, seizures, lactic acidosis, brain atrophy and MRI signal changes in the basal ganglia. Both children were compound heterozygotes for novel mutations in the human bc1 synthesis like (BCS1L) gene, which encodes an AAA mitochondrial protein putatively involved in both iron homeostasis and complex III assembly. The pathogenic role of the mutations was confirmed by complementation assays, using a 
Bcs1 strain of Saccharomyces cerevisiae. By investigating complex III assembly and the structural features of the BCS1L gene product in skeletal muscle, cultured fibroblasts and lymphoblastoid cell lines from our patients, we have demonstrated, for the first time in a mammalian system, that a major function of BCS1L is to promote the maturation of complex III and, more specifically, the incorporation of the Rieske iron–sulfur protein into the nascent complex. Defective BCS1L leads to the formation of a catalytically inactive, structurally unstable complex III. We have also shown that BCS1L is contained within a high-molecular-weight supramolecular complex which is clearly distinct from complex III intermediates.