Impaired complex I repair causes recessive Leber’s hereditary optic neuropathy
Sarah L. Stenton, Н Л Шеремет, Claudia B. Catarino, N.A. Andreeva, Zahra Assouline, Piero Barboni, Ortal Barel, Riccardo Berutti, Igor Bychkov, Leonardo Caporali, Mariantonietta Capristo, Michele Carbonelli, Maria Lucia Cascavilla, Peter Charbel Issa, Peter Freisinger, S. Gerber, Daniele Ghezzi, Elisabeth Graf, Juliana Heidler, Maja Hempel, Elise Héon, Y.S. Itkis, Elisheva Javasky, Josseline Kaplan, Robert Kopajtich, Cornelia Kornblum, Réka Kovács-Nagy, Tatiana Krylova, Wolfram S. Kunz, Chiara La Morgia, Costanza Lamperti, Christina Ludwig, Pedro Felipe Malacarne, Alessandra Maresca, Johannes A. Mayr, Jana Meisterknecht, Tatiana A. Nevinitsyna, Flavia Palombo, Ben Pode‐Shakked, M.S. Shmelkova, Tim M. Strom, Francesca Tagliavini, Michal Tzadok, Amelie T. van der Ven, Catherine Vignal, Matias Wagner, Ekaterina Zakharova, N.V. Zhorzholadze, Jean‐Michel Rozet, Valério Carelli, Polina 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.