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Stenton, S. ; Sheremet, N.L.* ; Catarino, C.B.* ; Andreeva, N.* ; Assouline, Z.* ; Barboni, P.* ; Barel, O.* ; Berutti, R. ; Bychkov, I.O.* ; Caporali, L.* ; Capristo, M.* ; Carbonelli, M.* ; Cascavilla, M.L.* ; Charbel Issa, P.* ; Freisinger, P.* ; Gerber, S.* ; Ghezzi, D.* ; Graf, E. ; Heidler, J.* ; Hempel, M.* ; Héon, E.* ; Itkis, Y.S.* ; Javasky, E.* ; Kaplan, J.* ; Kopajtich, R. ; Kornblum, C.* ; Kovács-Nagy, R.* ; Krylova, T.* ; Kunz, W.S.* ; La Morgia, C.* ; Lamperti, C.* ; Ludwig, C.* ; Malacarne, P.F.* ; Maresca, A.* ; Mayr, J.A.* ; Meisterknecht, J.* ; Nevinitsyna, T.* ; Palombo, F.* ; Pode-Shakked, B.* ; Shmelkova, M.S.* ; Strom, T.M.* ; Tagliavini, F.* ; Tzadok, M.* ; van der Ven, A.T.* ; Vignal-Clermont, C.* ; Wagner, M. ; Zakharova, E.* ; Zhorzholadze, N.* ; Rozet, J.M.* ; Carelli, V.* ; Tsygankova, P.* ; Klopstock, T.* ; Wittig, I.* ; Prokisch, H.

Impaired complex I repair causes recessive Leber's hereditary optic neuropathy.

J. Clin. Invest. 131:e138267 (2021)
Publ. Version/Full Text Postprint DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Genetic Diseases ; Genetics ; Neuroscience; Lhon/melas Overlap Syndrome; Mitochondrial; Identification; Mutations; Idebenone; Pathway
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Journal Journal of Clinical Investigation
Quellenangaben Volume: 131, Issue: 6, Pages: , Article Number: e138267 Supplement: ,
Publisher American Society of Clinical Investigation
Publishing Place 2015 Manchester Rd, Ann Arbor, Mi 48104 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Institute of Human Genetics (IHG)
Grants Horizon2020 through ERA PerMed project PerMiM
German BMBF
Horizon2020 through the ERare project GENOMIT
Italian Ministry of Health
Deutsche Forschungsgemeinschaft (DFG)
Cardio Pulmonary Institute (CPI) of the DFG
National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC, Oxford, United Kingdom)
Austrian Science Fund (FWF)
German Federal Ministry of Education and Research (BMBF, Bonn, Germany)