Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency.
Haack TB., Danhauser K., Haberberger B., Hoser J., Strecker V., Boehm D., Uziel G., Lamantea E., Invernizzi F., Poulton J., Rolinski B., Iuso A., Biskup S., Schmidt T., Mewes HW., Wittig I., Meitinger T., Zeviani M., Prokisch H.
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.