Stenton, Sarah L; Sheremet, Natalia L; Catarino, Claudia B; Andreeva, Natalia A; Assouline, Zahra; Barboni, Piero; Barel, Ortal; Berutti, Riccardo; Bychkov, Igor; Caporali, Leonardo; Capristo, Mariantonietta; Carbonelli, Michele; Cascavilla, Maria L; Charbel Issa, Peter; Freisinger, Peter; Gerber, Sylvie; Ghezzi, Daniele; Graf, Elisabeth; Heidler, Juliana; Hempel, Maja; Heon, Elise; Itkis, Yulya S; Javasky, Elisheva; Kaplan, Josseline; Kopajtich, Robert; Kornblum, Cornelia; Kovacs-Nagy, Reka; Krylova, Tatiana D; Kunz, Wolfram S; La Morgia, Chiara; Lamperti, Costanza; Ludwig, Christina; Malacarne, Pedro F; Maresca, Alessandra; Mayr, Johannes A; Meisterknecht, Jana; Nevinitsyna, Tatiana A; 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 Y; Zhorzholadze, Nino V; Rozet, Jean-Michel; Carelli, Valerio; Tsygankova, Polina G; Klopstock, Thomas; Wittig, Ilka; Prokisch, Holger     «

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

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.      «

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...     »