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@ARTICLE{Stenton:157727,
      author       = {Stenton, Sarah L and Sheremet, Natalia L and Catarino,
                      Claudia B and Andreeva, Natalia A and Assouline, Zahra and
                      Barboni, Piero and Barel, Ortal and Berutti, Riccardo and
                      Bychkov, Igor and Caporali, Leonardo and Capristo,
                      Mariantonietta and Carbonelli, Michele and Cascavilla, Maria
                      L and Charbel Issa, Peter and Freisinger, Peter and Gerber,
                      Sylvie and Ghezzi, Daniele and Graf, Elisabeth and Heidler,
                      Juliana and Hempel, Maja and Heon, Elise and Itkis, Yulya S
                      and Javasky, Elisheva and Kaplan, Josseline and Kopajtich,
                      Robert and Kornblum, Cornelia and Kovacs-Nagy, Reka and
                      Krylova, Tatiana D and Kunz, Wolfram S and La Morgia, Chiara
                      and Lamperti, Costanza and Ludwig, Christina and Malacarne,
                      Pedro F and Maresca, Alessandra and Mayr, Johannes A and
                      Meisterknecht, Jana and Nevinitsyna, Tatiana A and Palombo,
                      Flavia and Pode-Shakked, Ben and Shmelkova, Maria S and
                      Strom, Tim M and Tagliavini, Francesca and Tzadok, Michal
                      and van der Ven, Amelie T and Vignal-Clermont, Catherine and
                      Wagner, Matias and Zakharova, Ekaterina Y and Zhorzholadze,
                      Nino V and Rozet, Jean-Michel and Carelli, Valerio and
                      Tsygankova, Polina G and Klopstock, Thomas and Wittig, Ilka
                      and Prokisch, Holger},
      title        = {{I}mpaired complex {I} repair causes recessive {L}eber's
                      hereditary optic neuropathy.},
      journal      = {The journal of clinical investigation},
      volume       = {131},
      number       = {6},
      issn         = {1558-8238},
      address      = {Ann Arbor, Mich.},
      publisher    = {ASCJ},
      reportid     = {DZNE-2021-01184},
      pages        = {e138267},
      year         = {2021},
      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     = {Adolescent / Adult / Cell Line / Child, Preschool /
                      Electron Transport Complex I: chemistry / Electron Transport
                      Complex I: metabolism / Female / Gene Knockout Techniques /
                      Genes, Recessive / HSP40 Heat-Shock Proteins: deficiency /
                      HSP40 Heat-Shock Proteins: genetics / HSP40 Heat-Shock
                      Proteins: metabolism / Homozygote / Humans / Male / Middle
                      Aged / Mutation / Optic Atrophy, Hereditary, Leber: genetics
                      / Optic Atrophy, Hereditary, Leber: metabolism / Pedigree /
                      Penetrance / Phenotype / Protein Subunits / Reactive Oxygen
                      Species: metabolism / Young Adult / Genetic diseases (Other)
                      / Genetics (Other) / Neuroscience (Other)},
      cin          = {AG Höglinger 2},
      ddc          = {610},
      cid          = {I:(DE-2719)1111015},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33465056},
      pmc          = {pmc:PMC7954600},
      doi          = {10.1172/JCI138267},
      url          = {https://pub.dzne.de/record/157727},
}