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

Journal article

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.

Authors: Haack, T; Danhauser, K; Haberberger, B; Hoser, J; Strecker, V

• Publication status: Published
• Journal: Nature genetics
• Volume: 42
• Issue: 12
• Pages: 1131-1134
• Publication date: 2010-12-01
• DOI: 10.1038/ng.706
• EISSN: 1546-1718
• ISSN: 1061-4036
• Language: English
• Keywords: Female; Humans; Riboflavin; Genetic Complementation Test; Amino Acid Sequence; Fibroblasts; Mutation; Sequence Analysis, DNA; Infant; Child; Transduction, Genetic; Cell Line; Exons; Electron Transport Complex I; Male; Molecular Sequence Data; Acyl-CoA Dehydrogenases; Child, Preschool; Electrophoresis, Gel, Two-Dimensional