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

Stenton, Sarah L.; Sheremet, Natalia L.; Catarino, Claudia B.; Andreeva, Natalia; Assouline, Zahra; Barboni, Piero; Barel, Ortal; Berutti, Riccardo; Bychkov, Igor O.; Caporali, Leonardo; Capristo, Mariantonietta; Carbonelli, Michele; Cascavilla, Maria Lucia; Charbel Issa, Peter; Freisinger, Peter; Gerber, Sylvie; Ghezzi, Daniele; Graf, Elisabeth; Heidler, Juliana; Hempel, Maja; Heon, Elise; Itkis, Yulia S.; Javasky, Elisheva; Kaplan, Josseline; Kopajtich, Robert; Kornblum, Cornelia; Kovacs-Nagy, Reka; Krylova, Tatiana; Kunz, Wolfram S.; La Morgia, Chiara; Lamperti, Costanza; Ludwig, Christina; Malacarne, Pedro F.; Maresca, Alessandra; Mayr, Johannes A.; Meisterknecht, Jana; Nevinitsyna, Tatiana; Palombo, Flavia; Pode-Shakked, Ben; Shmelkova, Maria S.; Strom, Tim M.; Tagliavini, Francesca; Tzadok, Michal; van der Ven, Amelie T.; Vignal-Clermont, Catherine; Wagner, Matias; Zakharova, Ekaterina; Zhorzholadze, Nino; Rozet, Jen-Michel; Carelli, Valerio; Tsygankova, Polina; Klopstock, Thomas; Wittig, Ilka; Prokisch, Holger     «

Stenton, Sarah L.; Sheremet, Natalia L.; Catarino, Claudia B.; Andreeva, Natalia; Assouline, Zahra; Barboni, Piero; Barel, Ortal; Berutti, Riccardo; Bychkov, Igor O.; Caporali, Leonardo; Capristo, Mariantonietta; Carbonelli, Michele; Cascavilla, Maria Lucia; Charbel Issa, Peter; Freisinger, Peter; Gerber, Sylvie; Ghezzi, Daniele; Graf, Elisabeth; Heidler, Juliana; Hempel, Maja; Heon, Elise; Itkis, Yulia S.; Javasky, Elisheva; Kaplan, Josseline; Kopajtich, Robert; Kornblum, Cornelia; Kovacs-Nagy,...     »

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 the mitochondrial DNA (mtDNA). A molecular diagnosis is reached in up to 95%, the vast majority of which are accounted for by three mutations within mitochondrial complex I (CI) 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 are recapitulated, including incomplete penetrance, male predominance, and significant idebenone responsivity. Moreover, by tracking protein turnover in patient-derived cell lines and a DNAJC30-knock-out cellular model, we measure reduced turnover of specific CI N-module subunits and a resultant impairment of CI function. This demonstrates DNAJC30 is to be a chaperone protein needed for the efficient exchange of CI subunits exposed to reactive oxygen species and integral to a mitochondrial CI repair mechanism, thereby providing the first example of a disease resulting from impaired exchange of assembled respiratory chain subunits.     «

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 the mitochondrial DNA (mtDNA). A molecular diagnosis is reached in up to 95%, the vast majority of which are accounted for by three mutations within mitochondrial complex I (CI) 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 nucl...     »