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

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

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  • 1Institute of Human Genetics, Helmholtz Zentrum M√ľnchen, German Research Center for Environmental Health, Neuherberg, Germany.


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.

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