Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency

Nat Genet. 2010 Dec;42(12):1131-4. doi: 10.1038/ng.706. Epub 2010 Nov 7.


An isolated defect of respiratory chain complex I activity is a frequent biochemical abnormality in mitochondrial disorders. Despite intensive investigation in recent years, in most instances, the molecular basis underpinning complex I defects remains unknown. We report whole-exome sequencing of a single individual with severe, isolated complex I deficiency. This analysis, followed by filtering with a prioritization of mitochondrial proteins, led us to identify compound heterozygous mutations in ACAD9, which encodes a poorly understood member of the mitochondrial acyl-CoA dehydrogenase protein family. We demonstrated the pathogenic role of the ACAD9 variants by the correction of the complex I defect on expression of the wildtype ACAD9 protein in fibroblasts derived from affected individuals. ACAD9 screening of 120 additional complex I-defective index cases led us to identify two additional unrelated cases and a total of five pathogenic ACAD9 alleles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl-CoA Dehydrogenases / chemistry
  • Acyl-CoA Dehydrogenases / genetics*
  • Amino Acid Sequence
  • Cell Line
  • Child
  • Child, Preschool
  • Electron Transport Complex I / deficiency*
  • Electron Transport Complex I / metabolism
  • Electrophoresis, Gel, Two-Dimensional
  • Exons / genetics*
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Genetic Complementation Test
  • Humans
  • Infant
  • Male
  • Molecular Sequence Data
  • Mutation / genetics*
  • Riboflavin / pharmacology
  • Sequence Analysis, DNA*
  • Transduction, Genetic


  • Acyl-CoA Dehydrogenases
  • ACAD9 protein, human
  • Electron Transport Complex I
  • Riboflavin