title: Sequence variants in four candidate genes (NIPSNAP1, GBAS, CHCHD1 and METT11D1) in patients with combined oxidative phosphorylation system deficiencies.
abstract: The oxidative phosphorylation (OXPHOS) system, comprising five enzyme complexes, is located in the inner membrane of mitochondria and is the final biochemical pathway in oxidative ATP production. Defects in this energy-generating system can cause a wide range of clinical symptoms; these diseases are often progressive and multisystemic. Numerous genes have been implicated in OXPHOS deficiencies and many mutations have been described. However, in a substantial number of patients with decreased enzyme activities of two or more OXPHOS complexes, no mutations in the mitochondrial DNA or in nuclear genes known to be involved in these disorders have been found. In this study, four nuclear candidate genes--NIPSNAP1, GBAS, CHCHD1 and METT11D1--were screened for mutations in 22 patients with a combined enzymatic deficiency of primarily the OXPHOS complexes I, III and IV to determine whether a mutation in one of these genes could explain the mitochondrial disorder. For each variant not yet reported as a polymorphism, 100 control samples were screened for the presence of the variant. This way we identified 14 new polymorphisms and 2 presumably non-pathogenic mutations. No mutations were found that could explain the mitochondrial disorder in the patients investigated in this study. Therefore, the genetic defect in these patients must be located in other nuclear genes involved in mtDNA maintenance, transcription or translation, in import, processing or degradation of nuclear encoded mitochondrial proteins, or in assembly of the OXPHOS system.
authors.affiliation: Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Smits
authors.forename: R J
authors.initials: RJ
authors.lastname: Rodenburg
authors.forename: J A M
authors.initials: JA
authors.lastname: Smeitink
authors.forename: L P
authors.initials: LP
authors.lastname: van den Heuvel
mesh_terms: D016022:Case-Control Studies; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D004734:Energy Metabolism / Q000235:genetics*; D005347:Fibroblasts / Q000201:enzymology; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008661:Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics*; D008780:Methyltransferases / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000201:enzymology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C495375:CHCHD1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C113197:NIPSNAP1 protein, human; C113390:NIPSNAP2 protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D008780:Methyltransferases