title: Mutation detection in four candidate genes (OXA1L, MRS2L, YME1L and MIPEP) for combined deficiencies in the oxidative phosphorylation system.
abstract: Mitochondria are the main energy-producing organelles of the cell. Five complexes embedded in the mitochondrial inner membrane, together constituting the oxidative phosphorylation (OXPHOS) system, comprise the final steps in cellular energy production. Many patients with a mitochondrial defect suffer from a so-called combined deficiency, meaning that the enzymatic activities of two or more complexes of the OXPHOS system are decreased. Numerous mutations have been described in nuclear genes that are involved in the functioning of a single complex of the OXPHOS system. However, little attention has been paid to patients with a deficiency of more than one complex of this particular system. In this study we have investigated four nuclear genes (OXA1L, MRS2L, YME1L and MIPEP) that might be involved in the pathology of combined enzymatic deficiencies of the OXPHOS system. Based on the results of yeast knockouts of these four proteins, we have sequenced the open reading frame of OXA1L in eight patients with an enzymatic deficiency of complexes I and IV. MRS2L, YME1L and MIPEP have been sequenced in three patients with a combined defect of complexes III and IV. No mutations were detected in these patients, showing that at least in these patients the OXPHOS system deficiency cannot be explained by a mutation in these four genes.
authors.affiliation: Nijmegen Centre for Mitochondrial Disorders, Department of Paediatrics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: M J H
authors.initials: MJ
authors.lastname: Coenen
authors.forename: J A M
authors.initials: JA
authors.lastname: Smeitink
authors.forename: R
authors.initials: R
authors.lastname: Smeets
authors.forename: F J M
authors.initials: FJ
authors.lastname: Trijbels
authors.forename: L P
authors.initials: LP
authors.lastname: van den Heuvel
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D027682:Cation Transport Proteins / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics*; D020224:Expressed Sequence Tags; D005347:Fibroblasts / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D016366:Open Reading Frames; D010100:Oxygen / Q000378:metabolism*; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D027682:Cation Transport Proteins; D018076:DNA, Complementary; C430096:MRS2 protein, human; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; C090858:OXA1 protein; D003576:Electron Transport Complex IV; D008666:Metalloendopeptidases; C410807:YME1L1 protein, human; C068038:mitochondrial intermediate peptidase; D000074183:ATPases Associated with Diverse Cellular Activities; D010100:Oxygen