Impaired complex I repair causes recessive Leber’s hereditary optic neuropathy
| Autor: | Yulya S. Itkis, Maja Hempel, Ben Pode-Shakked, Piero Barboni, N.L. Sheremet, Polina G. Tsygankova, Riccardo Berutti, Valerio Carelli, Chiara La Morgia, Daniele Ghezzi, Leonardo Caporali, Jean-Michel Rozet, Natalia A. Andreeva, Amelie T van der Ven, Peter Charbel Issa, Wolfram S. Kunz, Sarah L. Stenton, Claudia B. Catarino, Johannes A. Mayr, Matias Wagner, Maria Lucia Cascavilla, Flavia Palombo, Reka Kovacs-Nagy, Ilka Wittig, Alessandra Maresca, Pedro Felipe Malacarne, Thomas Klopstock, Costanza Lamperti, Sylvie Gerber, Cornelia Kornblum, Holger Prokisch, Nino V. Zhorzholadze, Jana Meisterknecht, Robert Kopajtich, Tatiana A. Nevinitsyna, Ekaterina Zakharova, Michele Carbonelli, Tatiana D. Krylova, Michal Tzadok, Elisabeth Graf, Zahra Assouline, Francesca Tagliavini, Josseline Kaplan, Maria S. Shmelkova, Mariantonietta Capristo, Elise Héon, Ortal Barel, Peter Freisinger, Elisheva Javasky, Igor Bychkov, Christina Ludwig, Tim M. Strom, Catherine Vignal-Clermont, Juliana Heidler |
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| Přispěvatelé: | Stenton S.L., Sheremet N.L., Catarino C.B., Andreeva N.A., Assouline Z., Barboni P., Barel O., Berutti R., Bychkov I., Caporali L., Capristo M., Carbonelli M., Cascavilla M.L., Charbel Issa P., Freisinger P., Gerber S., Ghezzi D., Graf E., Heidler J., Hempel M., Heon E., Itkis Y.S., Javasky E., Kaplan J., Kopajtich R., Kornblum C., Kovacs-Nagy R., Krylova T.D., Kunz W.S., La Morgia C., Lamperti C., Ludwig C., Malacarne P.F., Maresca A., Mayr J.A., Meisterknecht J., Nevinitsyna T.A., 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.Y., Zhorzholadze N.V., Rozet J.-M., Carelli V., Tsygankova P.G., Klopstock T., Wittig I., Prokisch H. |
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine chemistry [Electron Transport Complex I] genetic structures deficiency [HSP40 Heat-Shock Proteins] Genetic disease Respiratory chain Penetrance metabolism [Optic Atrophy Hereditary Leber] Gene Knockout Techniques metabolism [HSP40 Heat-Shock Proteins] 0302 clinical medicine Idebenone metabolism [Reactive Oxygen Species] Protein Subunit Genetics Homozygote Gene Knockout Technique Leber's hereditary optic neuropathy General Medicine Middle Aged Pedigree Phenotype Child Preschool 030220 oncology & carcinogenesis Female Reactive Oxygen Specie genetics [HSP40 Heat-Shock Proteins] Genetic diseases Human medicine.drug Adult congenital hereditary and neonatal diseases and abnormalities Mitochondrial DNA Adolescent Mitochondrial disease Genes Recessive Optic Atrophy Hereditary Leber Biology Cell Line Young Adult 03 medical and health sciences Genetic medicine Humans ddc:610 metabolism [Electron Transport Complex I] Gene Electron Transport Complex I Point mutation nutritional and metabolic diseases HSP40 Heat-Shock Proteins medicine.disease eye diseases Protein Subunits 030104 developmental biology genetics [Optic Atrophy Hereditary Leber] Mutation Commentary HSP40 Heat-Shock Protein Reactive Oxygen Species Neuroscience |
| Zdroj: | The journal of clinical investigation 131(6), e138267 (2021). doi:10.1172/JCI138267 J Clin Invest |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci138267 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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