title: X-linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy.
abstract: OBJECTIVE
  Mitochondrial complex I deficiency is the commonest diagnosed respiratory chain defect, being genetically heterogeneous. The male preponderance of previous patient cohorts suggested an X-linked underlying genetic defect. We investigated mutations in the X-chromosomal complex I structural genes, NDUFA1 and NDUFB11, as a novel cause of mitochondrial encephalomyopathy.
  
  
  METHODS
  We sequenced 12 nuclear genes and the mitochondrial DNA-encoded complex I genes in 26 patients with respiratory chain complex I defect. Novel mutations were confirmed by polymerase chain reaction restriction length polymorphism. Assembly/stability studies in fibroblasts were performed using two-dimensional blue native gel electrophoresis.
  
  
  RESULTS
  Two novel p.Gly8Arg and p.Arg37Ser hemizygous mutations in NDUFA1 were identified in two unrelated male patients presenting with Leigh's syndrome and with myoclonic epilepsy and developmental delay, respectively. Two-dimensional blue native gel electrophoresis showed decreased levels of intact complex I with no accumulation of lower molecular weight subcomplexes, indicating that assembly, stability, or both are compromised.
  
  
  CONCLUSIONS
  Mutations in the X-linked NDUFA1 gene result in complex I defect and encephalomyopathy. Assembly/stability analysis might give an explanation for the different clinical phenotypes and become useful for future diagnostic purposes.
authors.affiliation: Centro de Investigación, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fernandez-Moreira
authors.forename: Cristina
authors.initials: C
authors.lastname: Ugalde
authors.forename: Roel
authors.initials: R
authors.lastname: Smeets
authors.forename: Richard J T
authors.initials: RJ
authors.lastname: Rodenburg
authors.forename: Eduardo
authors.initials: E
authors.lastname: Lopez-Laso
authors.forename: Maria L
authors.initials: ML
authors.lastname: Ruiz-Falco
authors.forename: Paz
authors.initials: P
authors.lastname: Briones
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Martin
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Smeitink
authors.forename: Joaquín
authors.initials: J
authors.lastname: Arenas
mesh_terms: D000818:Animals; D001120:Arginine / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D042967:Electron Transport Complex I / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D005260:Female; D050172:Genes, X-Linked; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics* / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009245:NADH Dehydrogenase / Q000235:genetics*; D016415:Sequence Alignment; D012694:Serine / Q000235:genetics
chemical_list: D012694:Serine; D001120:Arginine; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C118736:NDUFA1 protein, human; D005998:Glycine