A constant and similar assembly defect of mitochondrial respiratory chain complex I allows rapid identification of NDUFS4 mutations in patients with Leigh syndrome

Biochim Biophys Acta. 2012 Jun;1822(6):1062-9. doi: 10.1016/j.bbadis.2012.01.013. Epub 2012 Feb 3.


Isolated complex I deficiency is a frequent cause of respiratory chain defects in childhood. In this study, we report our systematic approach with blue native PAGE (BN-PAGE) to study mitochondrial respiratory chain assembly in skin fibroblasts from patients with Leigh syndrome and CI deficiency. We describe five new NDUFS4 patients with a similar and constant abnormal BN-PAGE profile and present a meta-analysis of the literature. All NDUFS4 mutations that have been tested with BN-PAGE result in a constant and similar abnormal assembly profile with a complete loss of the fully assembled complex I usually due to a truncated protein and the loss of its canonical cAMP dependent protein kinase phosphorylation consensus site. We also report the association of abnormal brain MRI images with this characteristic BN-PAGE profile as the hallmarks of NDUFS4 mutations and the first founder NDUFS4 mutations in the North-African population.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / pathology
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Electron Transport Complex I / deficiency
  • Electron Transport Complex I / genetics*
  • Electron Transport Complex I / metabolism
  • Female
  • Fibroblasts / metabolism
  • Humans
  • Infant
  • Leigh Disease / genetics*
  • Leigh Disease / metabolism
  • Leigh Disease / pathology
  • Male
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Diseases / pathology
  • Mutation
  • NADH Dehydrogenase / genetics*
  • Phosphorylation
  • Skin / metabolism


  • NADH Dehydrogenase
  • Cyclic AMP-Dependent Protein Kinases
  • Electron Transport Complex I
  • NDUFS4 protein, human