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Mutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9
  1. Tobias B Haack1,2,
  2. Florence Madignier2,
  3. Martina Herzer2,
  4. Eleonora Lamantea3,
  5. Katharina Danhauser2,
  6. Federica Invernizzi3,
  7. Johannes Koch4,
  8. Martin Freitag2,
  9. Rene Drost2,
  10. Ingo Hillier2,
  11. Birgit Haberberger2,
  12. Johannes A Mayr4,
  13. Uwe Ahting5,
  14. Valeria Tiranti3,
  15. Agnes Rötig6,
  16. Arcangela Iuso1,
  17. Rita Horvath7,
  18. Marketa Tesarova8,
  19. Ivo Baric9,
  20. Graziella Uziel10,
  21. Boris Rolinski5,
  22. Wolfgang Sperl4,
  23. Thomas Meitinger1,2,
  24. Massimo Zeviani3,
  25. Peter Freisinger11,
  26. Holger Prokisch1,2
  1. 1Institute of Human Genetics, Technische Universität München, Munich, Germany
  2. 2Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  3. 3Unit of Molecular Neurogenetics, Neurological Institute ‘Carlo Besta’-IRCCS Foundation, Milan, Italy
  4. 4Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
  5. 5Städtisches Klinikum München GmbH, Department Klinische Chemie, Munich, Germany
  6. 6Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
  7. 7Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
  8. 8Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic
  9. 9Department of Pediatrics, University Hospital Center Zagreb and School of Medicine, Zagreb, Croatia
  10. 10Unit of Child Neurology, Neurological Institute ‘Carlo Besta’-IRCCS Foundation, Milan, Italy
  11. 11Department of Paediatrics, Technische Universität München, Munich, Germany
  1. Correspondence to Dr Holger Prokisch, Institute of Human Genetics, Technische Universität München, Trogerstrasse 32, 81675 Munich, Germany; prokisch{at}


Background Mitochondrial complex I deficiency is the most common cause of mitochondrial disease in childhood. Identification of the molecular basis is difficult given the clinical and genetic heterogeneity. Most patients lack a molecular definition in routine diagnostics.

Methods A large-scale mutation screen of 75 candidate genes in 152 patients with complex I deficiency was performed by high-resolution melting curve analysis and Sanger sequencing. The causal role of a new disease allele was confirmed by functional complementation assays. The clinical phenotype of patients carrying mutations was documented using a standardised questionnaire.

Results Causative mutations were detected in 16 genes, 15 of which had previously been associated with complex I deficiency: three mitochondrial DNA genes encoding complex I subunits, two mitochondrial tRNA genes and nuclear DNA genes encoding six complex I subunits and four assembly factors. For the first time, a causal mutation is described in NDUFB9, coding for a complex I subunit, resulting in reduction in NDUFB9 protein and both amount and activity of complex I. These features were rescued by expression of wild-type NDUFB9 in patient-derived fibroblasts.

Conclusion Mutant NDUFB9 is a new cause of complex I deficiency. A molecular diagnosis related to complex I deficiency was established in 18% of patients. However, most patients are likely to carry mutations in genes so far not associated with complex I function. The authors conclude that the high degree of genetic heterogeneity in complex I disorders warrants the implementation of unbiased genome-wide strategies for the complete molecular dissection of mitochondrial complex I deficiency.

  • Mitochondrial complex I deficiency
  • high resolution melting curve analysis
  • lentiviral complementation
  • NDUFB9
  • genetic screening/counselling
  • molecular genetics
  • metabolic disorders
  • genetics
  • Complex I, neurology
  • neurosciences
  • neurology
  • neuromuscular disease
  • muscle disease
  • clinical genetics
  • endocrinology

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  • TBH, FM, MH and EL contributed equally to this work.

  • Funding TM and HP 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) and the German Federal Ministry of Education and Research (BMBF) funded German Center for Diabetes Research (DZD e.V.) and Systems Biology of Metabotypes grant (SysMBo #0315494A). EL, FI, TM, MZ and HP were supported by the grant RF-INN-2007-634163 from the Italian Ministry of Health. TM, PF and HP were supported by the BMBF funded German Network for Mitochondrial Disorders (mitoNET #01GM0867). EL, FI and MZ were supported by the Pierfranco and Luisa Mariani Foundation Italy, Fondazione Telethon Italy grants number GGP07019 and GGPP10005, Fondazione MitoCon-ONLUS, Fondazione Giuseppe Tomasello–ONLUS, and grant RF-INN-2007-634163. JAM and WS were supported by the Österreichische Nationalbank-Jubiläumsfonds grant number 12568 and the Vereinigung zur Pädiatrischen Forschung und Fortbildung Salzburg.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics committee, Faculty of Medicine, Technical University of Munich.

  • Provenance and peer review Not commissioned; externally peer reviewed.