Home > Publications Database > Impaired complex I repair causes recessive Leber's hereditary optic neuropathy. > print

001     157727
005     20240529143840.0
024 7 _ |a 10.1172/JCI138267
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024 7 _ |a pmid:33465056
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024 7 _ |a pmc:PMC7954600
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024 7 _ |a 0021-9738
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024 7 _ |a 1558-8238
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024 7 _ |a altmetric:98020578
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037 _ _ |a DZNE-2021-01184
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Stenton, Sarah L
|b 0
245 _ _ |a Impaired complex I repair causes recessive Leber's hereditary optic neuropathy.
260 _ _ |a Ann Arbor, Mich.
|c 2021
|b ASCJ
336 7 _ |a article
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336 7 _ |a Output Types/Journal article
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336 7 _ |a Journal Article
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|s 1632213999_9133
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a 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.
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650 _ 7 |a Genetic diseases
|2 Other
650 _ 7 |a Genetics
|2 Other
650 _ 7 |a Neuroscience
|2 Other
650 _ 2 |a Adolescent
|2 MeSH
650 _ 2 |a Adult
|2 MeSH
650 _ 2 |a Cell Line
|2 MeSH
650 _ 2 |a Child, Preschool
|2 MeSH
650 _ 2 |a Electron Transport Complex I: chemistry
|2 MeSH
650 _ 2 |a Electron Transport Complex I: metabolism
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Gene Knockout Techniques
|2 MeSH
650 _ 2 |a Genes, Recessive
|2 MeSH
650 _ 2 |a HSP40 Heat-Shock Proteins: deficiency
|2 MeSH
650 _ 2 |a HSP40 Heat-Shock Proteins: genetics
|2 MeSH
650 _ 2 |a HSP40 Heat-Shock Proteins: metabolism
|2 MeSH
650 _ 2 |a Homozygote
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Middle Aged
|2 MeSH
650 _ 2 |a Mutation
|2 MeSH
650 _ 2 |a Optic Atrophy, Hereditary, Leber: genetics
|2 MeSH
650 _ 2 |a Optic Atrophy, Hereditary, Leber: metabolism
|2 MeSH
650 _ 2 |a Pedigree
|2 MeSH
650 _ 2 |a Penetrance
|2 MeSH
650 _ 2 |a Phenotype
|2 MeSH
650 _ 2 |a Protein Subunits
|2 MeSH
650 _ 2 |a Reactive Oxygen Species: metabolism
|2 MeSH
650 _ 2 |a Young Adult
|2 MeSH
700 1 _ |a Sheremet, Natalia L
|b 1
700 1 _ |a Catarino, Claudia B
|b 2
700 1 _ |a Andreeva, Natalia A
|b 3
700 1 _ |a Assouline, Zahra
|b 4
700 1 _ |a Barboni, Piero
|b 5
700 1 _ |a Barel, Ortal
|b 6
700 1 _ |a Berutti, Riccardo
|b 7
700 1 _ |a Bychkov, Igor
|b 8
700 1 _ |a Caporali, Leonardo
|b 9
700 1 _ |a Capristo, Mariantonietta
|b 10
700 1 _ |a Carbonelli, Michele
|b 11
700 1 _ |a Cascavilla, Maria L
|b 12
700 1 _ |a Charbel Issa, Peter
|b 13
700 1 _ |a Freisinger, Peter
|b 14
700 1 _ |a Gerber, Sylvie
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700 1 _ |a Ghezzi, Daniele
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700 1 _ |a Graf, Elisabeth
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700 1 _ |a Heidler, Juliana
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700 1 _ |a Hempel, Maja
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700 1 _ |a Heon, Elise
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700 1 _ |a Itkis, Yulya S
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700 1 _ |a Javasky, Elisheva
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700 1 _ |a Kaplan, Josseline
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700 1 _ |a Kopajtich, Robert
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700 1 _ |a Kornblum, Cornelia
|b 25
700 1 _ |a Kovacs-Nagy, Reka
|b 26
700 1 _ |a Krylova, Tatiana D
|b 27
700 1 _ |a Kunz, Wolfram S
|b 28
700 1 _ |a La Morgia, Chiara
|b 29
700 1 _ |a Lamperti, Costanza
|b 30
700 1 _ |a Ludwig, Christina
|b 31
700 1 _ |a Malacarne, Pedro F
|b 32
700 1 _ |a Maresca, Alessandra
|b 33
700 1 _ |a Mayr, Johannes A
|b 34
700 1 _ |a Meisterknecht, Jana
|b 35
700 1 _ |a Nevinitsyna, Tatiana A
|b 36
700 1 _ |a Palombo, Flavia
|b 37
700 1 _ |a Pode-Shakked, Ben
|b 38
700 1 _ |a Shmelkova, Maria S
|b 39
700 1 _ |a Strom, Tim M
|b 40
700 1 _ |a Tagliavini, Francesca
|b 41
700 1 _ |a Tzadok, Michal
|b 42
700 1 _ |a van der Ven, Amelie T
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700 1 _ |a Vignal-Clermont, Catherine
|b 44
700 1 _ |a Wagner, Matias
|b 45
700 1 _ |a Zakharova, Ekaterina Y
|b 46
700 1 _ |a Zhorzholadze, Nino V
|b 47
700 1 _ |a Rozet, Jean-Michel
|b 48
700 1 _ |a Carelli, Valerio
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700 1 _ |a Tsygankova, Polina G
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700 1 _ |a Klopstock, Thomas
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700 1 _ |a Wittig, Ilka
|b 52
700 1 _ |a Prokisch, Holger
|b 53
773 _ _ |a 10.1172/JCI138267
|g Vol. 131, no. 6, p. e138267
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|t The journal of clinical investigation
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856 4 _ |u https://www.jci.org/articles/view/138267
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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