2. Academic Validation
  3. Impaired complex I repair causes recessive Leber's hereditary optic neuropathy

Impaired complex I repair causes recessive Leber's hereditary optic neuropathy

  • J Clin Invest. 2021 Mar 15;131(6):e138267. doi: 10.1172/JCI138267.
Sarah L Stenton 1 2,  Natalia L Sheremet 3,  Claudia B Catarino 4,  Natalia A Andreeva 3,  Zahra Assouline 5,  Piero Barboni 6,  Ortal Barel 7 8 9,  Riccardo Berutti 1 2,  Igor Bychkov 10,  Leonardo Caporali 11,  Mariantonietta Capristo 11,  Michele Carbonelli 11,  Maria L Cascavilla 6,  Peter Charbel Issa 12 13,  Peter Freisinger 14,  Sylvie Gerber 15,  Daniele Ghezzi 16 17,  Elisabeth Graf 1 2,  Juliana Heidler 18,  Maja Hempel 19,  Elise Heon 20,  Yulya S Itkis 10,  Elisheva Javasky 7 8 9,  Josseline Kaplan 15,  Robert Kopajtich 1 2,  Cornelia Kornblum 21,  Reka Kovacs-Nagy 1 22,  Tatiana D Krylova 10,  Wolfram S Kunz 23,  Chiara La Morgia 11 24,  Costanza Lamperti 16,  Christina Ludwig 25,  Pedro F Malacarne 26,  Alessandra Maresca 11,  Johannes A Mayr 27,  Jana Meisterknecht 18,  Tatiana A Nevinitsyna 3,  Flavia Palombo 11,  Ben Pode-Shakked 8 28 29,  Maria S Shmelkova 3,  Tim M Strom 1,  Francesca Tagliavini 11,  Michal Tzadok 8 30,  Amelie T van der Ven 19,  Catherine Vignal-Clermont 31,  Matias Wagner 1 2,  Ekaterina Y Zakharova 10,  Nino V Zhorzholadze 3,  Jean-Michel Rozet 15,  Valerio Carelli 11 24,  Polina G Tsygankova 10,  Thomas Klopstock 4 32 33,  Ilka Wittig 18 34,  Holger Prokisch 1 2
Affiliations

Affiliations

  • 1 Institute of Human Genetics, School of Medicine, Technische Universität München, Munich, Germany.
  • 2 Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
  • 3 Federal State Budgetary Institution of Science "Research Institute of Eye Diseases," Moscow, Russia.
  • 4 Department of Neurology, Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-Universität München, Munich, Germany.
  • 5 Fédération de Génétique et Institut Imagine, Université Paris Descartes, Hôpital Necker Enfants Malades, Paris, France.
  • 6 Scientific Institute San Raffaele, Milan, Italy.
  • 7 Genomics Unit, Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
  • 8 Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
  • 9 Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Israel.
  • 10 Research Centre for Medical Genetics, Moscow, Russia.
  • 11 IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
  • 12 Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.
  • 13 Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
  • 14 Department of Pediatrics, Klinikum am Steinenberg, Reutlingen, Germany.
  • 15 Laboratory Genetics in Ophthalmology (LGO), INSERM UMR1163 - Institute of Genetic Diseases, Imagine. Paris, France.
  • 16 Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
  • 17 Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
  • 18 Functional Proteomics, Medical School, Goethe University, Frankfurt am Main, Germany.
  • 19 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 20 The Hospital for Sick Children, Department of Ophthalmology and Vision Sciences, The University of Toronto, Toronto, Canada.
  • 21 Department of Neurology, University Hospital Bonn, Bonn, Germany.
  • 22 Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
  • 23 Department of Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.
  • 24 Unit of Neurology, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
  • 25 Bavarian Center for Biomolecular Mass Spectrometry (BayBioMS), Technische Universität München, Munich, Germany.
  • 26 Institute for Cardiovascular Physiology, Goethe-University Frankfurt, Frankfurt am Main, Germany.
  • 27 Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University Salzburg, Salzburg, Austria.
  • 28 Institute for Rare Diseases.
  • 29 Talpiot Medical Leadership Program, and.
  • 30 Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
  • 31 Ophthalmology Department, Centre National d'Ophtalmologie des Qinze-Vingts, Paris, France.
  • 32 German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
  • 33 Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
  • 34 German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Frankfurt, Germany.
PMID: 33465056 DOI: 10.1172/JCI138267
Abstract

Leber's hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was the first to be genetically defined by a point mutation in mitochondrial DNA (mtDNA). A molecular diagnosis is achieved in up to 95% of cases, the vast majority of which are accounted for by 3 mutations within mitochondrial complex I subunit-encoding genes in the mtDNA (mtLHON). Here, we resolve the enigma of LHON in the absence of pathogenic mtDNA mutations. We describe biallelic mutations in a nuclear encoded gene, DNAJC30, in 33 unsolved patients from 29 families and establish an autosomal recessive mode of inheritance for LHON (arLHON), which to date has been a prime example of a maternally inherited disorder. Remarkably, all hallmarks of mtLHON were recapitulated, including incomplete penetrance, male predominance, and significant idebenone responsivity. Moreover, by tracking protein turnover in patient-derived cell lines and a DNAJC30-knockout cellular model, we measured reduced turnover of specific complex I N-module subunits and a resultant impairment of complex I function. These results demonstrate that DNAJC30 is a chaperone protein needed for the efficient exchange of complex I subunits exposed to Reactive Oxygen Species and integral to a mitochondrial complex I repair mechanism, thereby providing the first example to our knowledge of a disease resulting from impaired exchange of assembled respiratory chain subunits.

Keywords

Genetic diseases; Genetics; Neuroscience.

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