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

Abstract

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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Figure 1
Figure 2: Cellular complementation experiment.
Figure 3: Complex I assembly in fibroblasts.
Figure 4: Effect of riboflavin treatment in fibroblasts.

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Acknowledgements

We are indebted to the subjects and their families involved in the study. We gratefully acknowledge the support of R. Hellinger, A. Löschner, M. Bada and F. Carrara in genotyping and cell culture work. Thanks to C. Fratter, M. Pike and S. Olpin. T.M. and H.P. were supported by the Impulse and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in an Ageing Society (HA-215), the German Federal Ministry of Education and Research (BMBF) funded German National Research Network (NGFNplus #01GS08134), German Network for Mitochondrial Disorders (mitoNET #01GM0862 and 01GM0867), German Center for Diabetes Research (DZD e.V.) and grant RF-INN-2007-634163 of the Italian Ministry of Health. H.-W.M., T.M. and H.P. were supported by the Systems Biology of Metabotypes (SysMBo #0315494A). I.W. was supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 815, Project Z1 (Redox-Proteomics), by the German Network for Mitochondrial Disorders (mitoNET #01GM0863) and by the Cluster of Excellence 'Macromolecular Complexes' at the Goethe-University (EXC 115). M.Z. was supported by the Pierfranco and Luisa Mariani Foundation Italy, Fondazione Telethon Italy grant number GGP07019, Fondazione Giuseppe Tomasello–ONLUS and grant RF-INN-2007-634163 of the Italian Ministry of Health. J.P. was supported by the Medical Research Council (UK) and the National Commissioning Group.

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Authors

Contributions

Project planning: T.M., M.Z., H.P. Experimental design: H.P. Review of phenotypes and sample collection: G.U., E.L., F.I., J.P. and B.R. Mutation screening: T.B.H., D.B. and S.B. Data analysis: T.B.H., J.H., T.S., H.-W.M. and H.P. Cell biology experiments: K.D., B.H., V.S., I.W. and A.I. Manuscript writing: T.B.H., T.M., M.Z. and H.P. Critical revision of the manuscript: all authors.

Corresponding authors

Correspondence to Massimo Zeviani or Holger Prokisch.

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The authors declare no competing financial interests.

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Supplementary Tables 1–4 and Supplementary Note (PDF 110 kb)

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Haack, T., Danhauser, K., Haberberger, B. et al. Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nat Genet 42, 1131–1134 (2010). https://doi.org/10.1038/ng.706

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