title: Respiratory chain complex I deficiency due to NDUFA12 mutations as a new cause of Leigh syndrome.
abstract: BACKGROUND
  This study investigated a girl with Leigh syndrome born to first-cousin parents of Pakistani descent with an isolated respiratory chain complex I deficiency in muscle and fibroblasts. Her early development was delayed, and from age 2 years she started losing motor abilities. Cerebral MRI showed basal ganglia lesions typical of Leigh syndrome.
  
  
  RESULTS
  A genome-wide search for homozygosity was performed with the Affymetrix GeneChip 50K Xba array. The analysis revealed several homozygous regions. Three candidate genes were identified, and in one of the genes, NDUFA12, a homozygous c.178C→T mutation leading to a premature stop codon (p.Arg60X) was found. Western blot analysis showed absence of NDUFA12 protein in patient fibroblasts and functional complementation by a baculovirus system showed restoration of complex I activity.
  
  
  CONCLUSIONS
  NDUFA12 mutations are apparently not a frequent cause of complex I deficiency, since mutations were not found by screening altogether 122 complex I deficient patients in two different studies. NDUFA12 encodes an accessory subunit of complex I and is a paralogue of NDUFAF2. Despite the complete absence of NDUFA12 protein, a fully assembled and enzymatically active complex I could be found, albeit in reduced amounts. This suggests that NDUFA12 is required either at a late step in the assembly of complex I, or in the stability of complex I.
authors: Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. elsebet.ostergaard@dadlnet.dk
authors: Elsebet
authors: E
authors: Ostergaard
authors: Richard J
authors: RJ
authors: Rodenburg
authors: Mariël
authors: M
authors: van den Brand
authors: Lise Lykke
authors: LL
authors: Thomsen
authors: Morten
authors: M
authors: Duno
authors: Mustafa
authors: M
authors: Batbayli
authors: Flemming
authors: F
authors: Wibrand
authors: Leo
authors: L
authors: Nijtmans