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000157727 0247_ $$2doi$$a10.1172/JCI138267
000157727 0247_ $$2pmid$$apmid:33465056
000157727 0247_ $$2pmc$$apmc:PMC7954600
000157727 0247_ $$2ISSN$$a0021-9738
000157727 0247_ $$2ISSN$$a1558-8238
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000157727 037__ $$aDZNE-2021-01184
000157727 041__ $$aEnglish
000157727 082__ $$a610
000157727 1001_ $$aStenton, Sarah L$$b0
000157727 245__ $$aImpaired complex I repair causes recessive Leber's hereditary optic neuropathy.
000157727 260__ $$aAnn Arbor, Mich.$$bASCJ$$c2021
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000157727 520__ $$aLeber'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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000157727 650_7 $$2Other$$aGenetic diseases
000157727 650_7 $$2Other$$aGenetics
000157727 650_7 $$2Other$$aNeuroscience
000157727 650_2 $$2MeSH$$aAdolescent
000157727 650_2 $$2MeSH$$aAdult
000157727 650_2 $$2MeSH$$aCell Line
000157727 650_2 $$2MeSH$$aChild, Preschool
000157727 650_2 $$2MeSH$$aElectron Transport Complex I: chemistry
000157727 650_2 $$2MeSH$$aElectron Transport Complex I: metabolism
000157727 650_2 $$2MeSH$$aFemale
000157727 650_2 $$2MeSH$$aGene Knockout Techniques
000157727 650_2 $$2MeSH$$aGenes, Recessive
000157727 650_2 $$2MeSH$$aHSP40 Heat-Shock Proteins: deficiency
000157727 650_2 $$2MeSH$$aHSP40 Heat-Shock Proteins: genetics
000157727 650_2 $$2MeSH$$aHSP40 Heat-Shock Proteins: metabolism
000157727 650_2 $$2MeSH$$aHomozygote
000157727 650_2 $$2MeSH$$aHumans
000157727 650_2 $$2MeSH$$aMale
000157727 650_2 $$2MeSH$$aMiddle Aged
000157727 650_2 $$2MeSH$$aMutation
000157727 650_2 $$2MeSH$$aOptic Atrophy, Hereditary, Leber: genetics
000157727 650_2 $$2MeSH$$aOptic Atrophy, Hereditary, Leber: metabolism
000157727 650_2 $$2MeSH$$aPedigree
000157727 650_2 $$2MeSH$$aPenetrance
000157727 650_2 $$2MeSH$$aPhenotype
000157727 650_2 $$2MeSH$$aProtein Subunits
000157727 650_2 $$2MeSH$$aReactive Oxygen Species: metabolism
000157727 650_2 $$2MeSH$$aYoung Adult
000157727 7001_ $$aSheremet, Natalia L$$b1
000157727 7001_ $$aCatarino, Claudia B$$b2
000157727 7001_ $$aAndreeva, Natalia A$$b3
000157727 7001_ $$aAssouline, Zahra$$b4
000157727 7001_ $$aBarboni, Piero$$b5
000157727 7001_ $$aBarel, Ortal$$b6
000157727 7001_ $$aBerutti, Riccardo$$b7
000157727 7001_ $$aBychkov, Igor$$b8
000157727 7001_ $$aCaporali, Leonardo$$b9
000157727 7001_ $$aCapristo, Mariantonietta$$b10
000157727 7001_ $$aCarbonelli, Michele$$b11
000157727 7001_ $$aCascavilla, Maria L$$b12
000157727 7001_ $$aCharbel Issa, Peter$$b13
000157727 7001_ $$aFreisinger, Peter$$b14
000157727 7001_ $$aGerber, Sylvie$$b15
000157727 7001_ $$aGhezzi, Daniele$$b16
000157727 7001_ $$aGraf, Elisabeth$$b17
000157727 7001_ $$aHeidler, Juliana$$b18
000157727 7001_ $$aHempel, Maja$$b19
000157727 7001_ $$aHeon, Elise$$b20
000157727 7001_ $$aItkis, Yulya S$$b21
000157727 7001_ $$aJavasky, Elisheva$$b22
000157727 7001_ $$aKaplan, Josseline$$b23
000157727 7001_ $$aKopajtich, Robert$$b24
000157727 7001_ $$aKornblum, Cornelia$$b25
000157727 7001_ $$aKovacs-Nagy, Reka$$b26
000157727 7001_ $$aKrylova, Tatiana D$$b27
000157727 7001_ $$aKunz, Wolfram S$$b28
000157727 7001_ $$aLa Morgia, Chiara$$b29
000157727 7001_ $$aLamperti, Costanza$$b30
000157727 7001_ $$aLudwig, Christina$$b31
000157727 7001_ $$aMalacarne, Pedro F$$b32
000157727 7001_ $$aMaresca, Alessandra$$b33
000157727 7001_ $$aMayr, Johannes A$$b34
000157727 7001_ $$aMeisterknecht, Jana$$b35
000157727 7001_ $$aNevinitsyna, Tatiana A$$b36
000157727 7001_ $$aPalombo, Flavia$$b37
000157727 7001_ $$aPode-Shakked, Ben$$b38
000157727 7001_ $$aShmelkova, Maria S$$b39
000157727 7001_ $$aStrom, Tim M$$b40
000157727 7001_ $$aTagliavini, Francesca$$b41
000157727 7001_ $$aTzadok, Michal$$b42
000157727 7001_ $$avan der Ven, Amelie T$$b43
000157727 7001_ $$aVignal-Clermont, Catherine$$b44
000157727 7001_ $$aWagner, Matias$$b45
000157727 7001_ $$aZakharova, Ekaterina Y$$b46
000157727 7001_ $$aZhorzholadze, Nino V$$b47
000157727 7001_ $$aRozet, Jean-Michel$$b48
000157727 7001_ $$aCarelli, Valerio$$b49
000157727 7001_ $$aTsygankova, Polina G$$b50
000157727 7001_ $$0P:(DE-2719)2810704$$aKlopstock, Thomas$$b51$$udzne
000157727 7001_ $$aWittig, Ilka$$b52
000157727 7001_ $$aProkisch, Holger$$b53
000157727 773__ $$0PERI:(DE-600)2018375-6$$a10.1172/JCI138267$$gVol. 131, no. 6, p. e138267$$n6$$pe138267$$tThe journal of clinical investigation$$v131$$x1558-8238$$y2021
000157727 8564_ $$uhttps://www.jci.org/articles/view/138267
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