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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)

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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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