Respiratory chain complex I deficiency due to NDUFA12 mutations as a new cause of Leigh syndrome

J Med Genet. 2011 Nov;48(11):737-40. doi: 10.1136/jmg.2011.088856. Epub 2011 May 26.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Child
  • Codon, Nonsense*
  • Consanguinity
  • DNA Mutational Analysis
  • Electron Transport / genetics
  • Electron Transport Complex I / deficiency*
  • Electron Transport Complex I / genetics
  • Female
  • Fibroblasts / enzymology*
  • Fibroblasts / pathology
  • Genetic Complementation Test
  • Genome-Wide Association Study
  • Homozygote
  • Humans
  • Leigh Disease / diagnosis
  • Leigh Disease / enzymology
  • Leigh Disease / genetics*
  • Mitochondria / enzymology*
  • Mitochondria / genetics
  • Mitochondria / pathology
  • Mitochondrial Proteins / deficiency
  • Mitochondrial Proteins / genetics*
  • Muscles / enzymology*
  • Muscles / pathology
  • Oligonucleotide Array Sequence Analysis


  • Codon, Nonsense
  • Mitochondrial Proteins
  • Electron Transport Complex I