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Respiratory chain complex I deficiency due to NDUFA12 mutations as a new cause of Leigh syndrome
  1. Elsebet Ostergaard1,
  2. Richard J Rodenburg2,
  3. Mariël van den Brand2,
  4. Lise Lykke Thomsen3,
  5. Morten Duno1,
  6. Mustafa Batbayli1,
  7. Flemming Wibrand1,
  8. Leo Nijtmans2
  1. 1Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
  2. 2Nijmegen Center for Mitochondrial Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  3. 3Department of Pediatrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
  1. Correspondence to Dr Elsebet Ostergaard, Department of Clinical Genetics 4062, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, Copenhagen 2100, Denmark; elsebet.ostergaard{at}dadlnet.dk

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.

Methods and 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.

Conclusion 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.

  • Metabolic disorders
  • molecular genetics

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Footnotes

  • Funding This work was supported by a grant from the Danish Medical Research Council.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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