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

TitleExome sequencing identifies ACAD9 mutations as a cause of complex I deficiency.
Publication TypeJournal Article
Year of Publication2010
AuthorsHaack, 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, H-W, Wittig, I, Meitinger, T, Zeviani, M, Prokisch, H
JournalNat Genet
Date Published2010 Dec
KeywordsAcyl-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

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.

Alternate JournalNat. Genet.
Citation Key10.1038/ng.706
PubMed ID21057504
Grant ListG0500695 / / Medical Research Council / United Kingdom
GGP07019 / / Telethon / Italy