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

Tobias B. Haack; Katharina Danhauser; Birgit Haberberger; Jonathan Hoser; Valentina Strecker; Detlef Boehm; Graziella Uziel; Eleonora Lamantea; Federica Invernizzi; Joanna Poulton; Boris Rolinski; Arcangela Iuso; Saskia Biskup; Thorsten Schmidt; Hans Werner Mewes; Ilka Wittig; Thomas Meitinger; Massimo Zeviani; Holger Prokisch

doi:10.1038/ng.706

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

Tobias B. Haack, Katharina Danhauser, Birgit Haberberger, Jonathan Hoser, Valentina Strecker, Detlef Boehm, Graziella Uziel, Eleonora Lamantea, Federica Invernizzi, Joanna Poulton, Boris Rolinski, Arcangela Iuso, Saskia Biskup, Thorsten Schmidt, Hans Werner Mewes, Ilka Wittig, Thomas Meitinger, Massimo Zeviani, Holger Prokisch

Research output: Contribution to journal › Article › peer-review

223 Scopus citations

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 Iĝ€"defective index cases led us to identify two additional unrelated cases and a total of five pathogenic ACAD9 alleles.

Original language	English
Pages (from-to)	1131-1134
Number of pages	4
Journal	Nature Genetics
Volume	42
Issue number	12
DOIs	https://doi.org/10.1038/ng.706
State	Published - Dec 2010

Access to Document

10.1038/ng.706

Cite this

Haack, T. B., 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. (2010). Exome sequencing identifies ACAD9 mutations as a cause of complex i deficiency. Nature Genetics, 42(12), 1131-1134. https://doi.org/10.1038/ng.706

@article{ea28894d1fb4468bb355650034777741,

title = "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 Iĝ€{"}defective index cases led us to identify two additional unrelated cases and a total of five pathogenic ACAD9 alleles.",

author = "Haack, {Tobias B.} and Katharina Danhauser and Birgit Haberberger and Jonathan Hoser and Valentina Strecker and Detlef Boehm and Graziella Uziel and Eleonora Lamantea and Federica Invernizzi and Joanna Poulton and Boris Rolinski and Arcangela Iuso and Saskia Biskup and Thorsten Schmidt and Mewes, {Hans Werner} and Ilka Wittig and Thomas Meitinger and Massimo Zeviani and Holger Prokisch",

note = "Funding Information: We are indebted to the subjects and their families involved in the study. We gratefully acknowledge the support of R. Hellinger, A. L{\"o}schner, 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 {\textquoteleft}Macromolecular Complexes{\textquoteright} 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.",

year = "2010",

month = dec,

doi = "10.1038/ng.706",

language = "English",

volume = "42",

pages = "1131--1134",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "12",

}

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 2010, 'Exome sequencing identifies ACAD9 mutations as a cause of complex i deficiency', Nature Genetics, vol. 42, no. 12, pp. 1131-1134. https://doi.org/10.1038/ng.706

TY - JOUR

T1 - Exome sequencing identifies ACAD9 mutations as a cause of complex i deficiency

AU - Haack, Tobias B.

AU - Danhauser, Katharina

AU - Haberberger, Birgit

AU - Hoser, Jonathan

AU - Strecker, Valentina

AU - Boehm, Detlef

AU - Uziel, Graziella

AU - Lamantea, Eleonora

AU - Invernizzi, Federica

AU - Poulton, Joanna

AU - Rolinski, Boris

AU - Iuso, Arcangela

AU - Biskup, Saskia

AU - Schmidt, Thorsten

AU - Mewes, Hans Werner

AU - Wittig, Ilka

AU - Meitinger, Thomas

AU - Zeviani, Massimo

AU - Prokisch, Holger

N1 - Funding Information: 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.

PY - 2010/12

Y1 - 2010/12

N2 - 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 Iĝ€"defective index cases led us to identify two additional unrelated cases and a total of five pathogenic ACAD9 alleles.

AB - 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 Iĝ€"defective index cases led us to identify two additional unrelated cases and a total of five pathogenic ACAD9 alleles.

UR - http://www.scopus.com/inward/record.url?scp=78649474742&partnerID=8YFLogxK

U2 - 10.1038/ng.706

DO - 10.1038/ng.706

M3 - Article

C2 - 21057504

AN - SCOPUS:78649474742

SN - 1061-4036

VL - 42

SP - 1131

EP - 1134

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

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

Abstract

Access to Document

Other files and links

Fingerprint

Cite this