title: Defective NDUFA9 as a novel cause of neonatally fatal complex I disease.
abstract: BACKGROUND
  Mitochondrial disorders are associated with abnormalities of the oxidative phosphorylation (OXPHOS) system and cause significant morbidity and mortality in the population. The extensive clinical and genetic heterogeneity of these disorders due to a broad variety of mutations in several hundreds of candidate genes, encoded by either the mitochondrial DNA (mtDNA) or nuclear DNA (nDNA), impedes a straightforward genetic diagnosis. A new disease gene is presented here, identified in a single Kurdish patient born from consanguineous parents with neonatally fatal Leigh syndrome and complex I deficiency.
  
  
  RESULTS
  Using homozygosity mapping and subsequent positional candidate gene analysis, a total region of 255.8 Mb containing 136 possible mitochondrial genes was identified. A pathogenic mutation was found in the complex I subunit encoding the NDUFA9 gene, changing a highly conserved arginine at position 321 to proline. This is the first disease-causing mutation ever reported for NDUFA9. Complex I activity was restored in fibroblasts of the patient by lentiviral transduction with wild type but not mutant NDUFA9, confirming that the mutation causes the complex I deficiency and related disease.
  
  
  CONCLUSIONS
  The data show that homozygosity mapping and candidate gene analysis remain an efficient way to detect mutations even in small consanguineous pedigrees with OXPHOS deficiency, especially when the enzyme deficiency in fibroblasts allows appropriate candidate gene selection and functional complementation.
authors: Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, Maastricht, The Netherlands. bianca.vanden.bosch@mumc.nl
authors: B J C
authors: BJ
authors: van den Bosch
authors: M
authors: M
authors: Gerards
authors: W
authors: W
authors: Sluiter
authors: A P A
authors: AP
authors: Stegmann
authors: E L C
authors: EL
authors: Jongen
authors: D M E I
authors: DM
authors: Hellebrekers
authors: R
authors: R
authors: Oegema
authors: E H
authors: EH
authors: Lambrichs
authors: H
authors: H
authors: Prokisch
authors: K
authors: K
authors: Danhauser
authors: K
authors: K
authors: Schoonderwoerd
authors: I F M
authors: IF
authors: de Coo
authors: H J M
authors: HJ
authors: Smeets
mesh_terms: D000595:Amino Acid Sequence; D002478:Cells, Cultured; D003241:Consanguinity; D004252:DNA Mutational Analysis; D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism; D017809:Fatal Outcome; D056726:Genetic Association Studies; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D007888:Leigh Disease / Q000175:diagnosis* / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D059906:Neuroimaging
chemical_list: D042967:Electron Transport Complex I; C571164:NDUFA9 protein, human