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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.

Original publication

DOI

10.1038/ng.706

Type

Journal article

Journal

Nat Genet

Publication Date

12/2010

Volume

42

Pages

1131 - 1134

Keywords

Acyl-CoA Dehydrogenases, Amino Acid Sequence, Cell Line, Child, Child, Preschool, Electron Transport Complex I, Electrophoresis, Gel, Two-Dimensional, Exons, Female, Fibroblasts, Genetic Complementation Test, Humans, Infant, Male, Molecular Sequence Data, Mutation, Riboflavin, Sequence Analysis, DNA, Transduction, Genetic