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.

Impaired complex I repair causes recessive Leber's hereditary optic neuropathy / S.L. Stenton, N.L. Sheremet, C.B. Catarino, N.A. Andreeva, Z. Assouline, P. Barboni, O. Barel, R. Berutti, I. Bychkov, L. Caporali, M. Capristo, M. Carbonelli, M.L. Cascavilla, P. Charbel Issa, P. Freisinger, S. Gerber, D. Ghezzi, E. Graf, J. Heidler, M. Hempel, E. Heon, Y.S. Itkis, E. Javasky, J. Kaplan, R. Kopajtich, C. Kornblum, R. Kovacs-Nagy, T.D. Krylova, W.S. Kunz, C. La Morgia, C. Lamperti, C. Ludwig, P.F. Malacarne, A. Maresca, J.A. Mayr, J. Meisterknecht, T.A. Nevinitsyna, F. Palombo, B. Pode-Shakked, M.S. Shmelkova, T.M. Strom, F. Tagliavini, M. Tzadok, A.T. van der Ven, C. Vignal-Clermont, M. Wagner, E.Y. Zakharova, N.V. Zhorzholadze, J. Rozet, V. Carelli, P.G. Tsygankova, T. Klopstock, I. Wittig, H. Prokisch. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 1558-8238. - 131:6(2021 Mar 15), pp. e138267.1-e138267.13. [10.1172/JCI138267]

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

D. Ghezzi;C. Lamperti;
2021-03-15

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.
Genetic diseases; Genetics; Neuroscience
Settore MED/03 - Genetica Medica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/863462
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