Impaired complex I repair causes recessive Leber's hereditary optic neuropathy
Sarah L Stenton, Natalia L Sheremet, Claudia B Catarino, Natalia A Andreeva, Zahra Assouline, Piero Barboni, Ortal Barel, Riccardo Berutti, Igor Bychkov, Leonardo Caporali, Mariantonietta Capristo, Michele Carbonelli, Maria L Cascavilla, Peter Charbel Issa, Peter Freisinger, Sylvie Gerber, Daniele Ghezzi, Elisabeth Graf, Juliana Heidler, Maja Hempel, Elise Heon, Yulya S Itkis, Elisheva Javasky, Josseline Kaplan, Robert Kopajtich, Cornelia Kornblum, Reka Kovacs-Nagy, Tatiana D Krylova, Wolfram S Kunz, Chiara La Morgia, Costanza Lamperti, Christina Ludwig, Pedro F Malacarne, Alessandra Maresca, Johannes A Mayr, Jana Meisterknecht, Tatiana A Nevinitsyna, Flavia Palombo, Ben Pode-Shakked, Maria S Shmelkova, Tim M Strom, Francesca Tagliavini, Michal Tzadok, Amelie T van der Ven, Catherine Vignal-Clermont, Matias Wagner, Ekaterina Y Zakharova, Nino V Zhorzholadze, Jean-Michel Rozet, Valerio Carelli, Polina G Tsygankova, Thomas Klopstock, Ilka Wittig, Holger Prokisch, Sarah L Stenton, Natalia L Sheremet, Claudia B Catarino, Natalia A Andreeva, Zahra Assouline, Piero Barboni, Ortal Barel, Riccardo Berutti, Igor Bychkov, Leonardo Caporali, Mariantonietta Capristo, Michele Carbonelli, Maria L Cascavilla, Peter Charbel Issa, Peter Freisinger, Sylvie Gerber, Daniele Ghezzi, Elisabeth Graf, Juliana Heidler, Maja Hempel, Elise Heon, Yulya S Itkis, Elisheva Javasky, Josseline Kaplan, Robert Kopajtich, Cornelia Kornblum, Reka Kovacs-Nagy, Tatiana D Krylova, Wolfram S Kunz, Chiara La Morgia, Costanza Lamperti, Christina Ludwig, Pedro F Malacarne, Alessandra Maresca, Johannes A Mayr, Jana Meisterknecht, Tatiana A Nevinitsyna, Flavia Palombo, Ben Pode-Shakked, Maria S Shmelkova, Tim M Strom, Francesca Tagliavini, Michal Tzadok, Amelie T van der Ven, Catherine Vignal-Clermont, Matias Wagner, Ekaterina Y Zakharova, Nino V Zhorzholadze, Jean-Michel Rozet, Valerio Carelli, Polina G Tsygankova, Thomas Klopstock, Ilka Wittig, Holger Prokisch
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.
Conflict of interest statement
Conflict of interest: CBC, CK, PB, CLM, TK, and VC have received research support, speaker honoraria, consulting fees, and travel reimbursement from Santhera Pharmaceuticals and GenSight Biologics.
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