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

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Impaired complex I repair causes recessive Leber's hereditary optic neuropathy. / Stenton, Sarah L; Sheremet, Natalia L; Catarino, Claudia B; Andreeva, Natalia A; Assouline, Zahra; Barboni, Piero; Barel, Ortal; Berutti, Riccardo; Bychkov, Igor; Caporali, Leonardo; Capristo, Mariantonietta; Carbonelli, Michele; Cascavilla, Maria L; Charbel Issa, Peter; Freisinger, Peter; Gerber, Sylvie; Ghezzi, Daniele; Graf, Elisabeth; Heidler, Juliana; Hempel, Maja; Heon, Elise; Itkis, Yulya S; Javasky, Elisheva; Kaplan, Josseline; Kopajtich, Robert; Kornblum, Cornelia; Kovacs-Nagy, Reka; Krylova, Tatiana D; Kunz, Wolfram S; La Morgia, Chiara; Lamperti, Costanza; Ludwig, Christina; Malacarne, Pedro F; Maresca, Alessandra; Mayr, Johannes A; Meisterknecht, Jana; Nevinitsyna, Tatiana A; Palombo, Flavia; Pode-Shakked, Ben; Shmelkova, Maria S; Strom, Tim M; Tagliavini, Francesca; Tzadok, Michal; van der Ven, Amelie T; Vignal-Clermont, Catherine; Wagner, Matias; Zakharova, Ekaterina Y; Zhorzholadze, Nino V; Rozet, Jean-Michel; Carelli, Valerio; Tsygankova, Polina G; Klopstock, Thomas; Wittig, Ilka; Prokisch, Holger.

in: J CLIN INVEST, Jahrgang 131, Nr. 6, e138267, 15.03.2021.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Stenton, SL, Sheremet, NL, Catarino, CB, Andreeva, NA, Assouline, Z, Barboni, P, Barel, O, Berutti, R, Bychkov, I, Caporali, L, Capristo, M, Carbonelli, M, Cascavilla, ML, Charbel Issa, P, Freisinger, P, Gerber, S, Ghezzi, D, Graf, E, Heidler, J, Hempel, M, Heon, E, Itkis, YS, Javasky, E, Kaplan, J, Kopajtich, R, Kornblum, C, Kovacs-Nagy, R, Krylova, TD, Kunz, WS, La Morgia, C, Lamperti, C, Ludwig, C, Malacarne, PF, Maresca, A, Mayr, JA, Meisterknecht, J, Nevinitsyna, TA, Palombo, F, Pode-Shakked, B, Shmelkova, MS, Strom, TM, Tagliavini, F, Tzadok, M, van der Ven, AT, Vignal-Clermont, C, Wagner, M, Zakharova, EY, Zhorzholadze, NV, Rozet, J-M, Carelli, V, Tsygankova, PG, Klopstock, T, Wittig, I & Prokisch, H 2021, 'Impaired complex I repair causes recessive Leber's hereditary optic neuropathy', J CLIN INVEST, Jg. 131, Nr. 6, e138267. https://doi.org/10.1172/JCI138267

APA

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., ... Prokisch, H. (2021). Impaired complex I repair causes recessive Leber's hereditary optic neuropathy. J CLIN INVEST, 131(6), [e138267]. https://doi.org/10.1172/JCI138267

Vancouver

Stenton SL, Sheremet NL, Catarino CB, Andreeva NA, Assouline Z, Barboni P et al. Impaired complex I repair causes recessive Leber's hereditary optic neuropathy. J CLIN INVEST. 2021 Mär 15;131(6). e138267. https://doi.org/10.1172/JCI138267

Bibtex

@article{3d644e3f3c7b45ceacb2712161711d2c,
title = "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy",
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.",
keywords = "Adolescent, Adult, Cell Line, Child, Preschool, Electron Transport Complex I/chemistry, Female, Gene Knockout Techniques, Genes, Recessive, HSP40 Heat-Shock Proteins/deficiency, Homozygote, Humans, Male, Middle Aged, Mutation, Optic Atrophy, Hereditary, Leber/genetics, Pedigree, Penetrance, Phenotype, Protein Subunits, Reactive Oxygen Species/metabolism, Young Adult",
author = "Stenton, {Sarah L} and Sheremet, {Natalia L} and Catarino, {Claudia B} and Andreeva, {Natalia A} and Zahra Assouline and Piero Barboni and Ortal Barel and Riccardo Berutti and Igor Bychkov and Leonardo Caporali and Mariantonietta Capristo and Michele Carbonelli and Cascavilla, {Maria L} and {Charbel Issa}, Peter and Peter Freisinger and Sylvie Gerber and Daniele Ghezzi and Elisabeth Graf and Juliana Heidler and Maja Hempel and Elise Heon and Itkis, {Yulya S} and Elisheva Javasky and Josseline Kaplan and Robert Kopajtich and Cornelia Kornblum and Reka Kovacs-Nagy and Krylova, {Tatiana D} and Kunz, {Wolfram S} and {La Morgia}, Chiara and Costanza Lamperti and Christina Ludwig and Malacarne, {Pedro F} and Alessandra Maresca and Mayr, {Johannes A} and Jana Meisterknecht and Nevinitsyna, {Tatiana A} and Flavia Palombo and Ben Pode-Shakked and Shmelkova, {Maria S} and Strom, {Tim M} and Francesca Tagliavini and Michal Tzadok and {van der Ven}, {Amelie T} and Catherine Vignal-Clermont and Matias Wagner and Zakharova, {Ekaterina Y} and Zhorzholadze, {Nino V} and Jean-Michel Rozet and Valerio Carelli and Tsygankova, {Polina G} and Thomas Klopstock and Ilka Wittig and Holger Prokisch",
year = "2021",
month = mar,
day = "15",
doi = "10.1172/JCI138267",
language = "English",
volume = "131",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "6",

}

RIS

TY - JOUR

T1 - Impaired complex I repair causes recessive Leber's hereditary optic neuropathy

AU - Stenton, Sarah L

AU - Sheremet, Natalia L

AU - Catarino, Claudia B

AU - Andreeva, Natalia A

AU - Assouline, Zahra

AU - Barboni, Piero

AU - Barel, Ortal

AU - Berutti, Riccardo

AU - Bychkov, Igor

AU - Caporali, Leonardo

AU - Capristo, Mariantonietta

AU - Carbonelli, Michele

AU - Cascavilla, Maria L

AU - Charbel Issa, Peter

AU - Freisinger, Peter

AU - Gerber, Sylvie

AU - Ghezzi, Daniele

AU - Graf, Elisabeth

AU - Heidler, Juliana

AU - Hempel, Maja

AU - Heon, Elise

AU - Itkis, Yulya S

AU - Javasky, Elisheva

AU - Kaplan, Josseline

AU - Kopajtich, Robert

AU - Kornblum, Cornelia

AU - Kovacs-Nagy, Reka

AU - Krylova, Tatiana D

AU - Kunz, Wolfram S

AU - La Morgia, Chiara

AU - Lamperti, Costanza

AU - Ludwig, Christina

AU - Malacarne, Pedro F

AU - Maresca, Alessandra

AU - Mayr, Johannes A

AU - Meisterknecht, Jana

AU - Nevinitsyna, Tatiana A

AU - Palombo, Flavia

AU - Pode-Shakked, Ben

AU - Shmelkova, Maria S

AU - Strom, Tim M

AU - Tagliavini, Francesca

AU - Tzadok, Michal

AU - van der Ven, Amelie T

AU - Vignal-Clermont, Catherine

AU - Wagner, Matias

AU - Zakharova, Ekaterina Y

AU - Zhorzholadze, Nino V

AU - Rozet, Jean-Michel

AU - Carelli, Valerio

AU - Tsygankova, Polina G

AU - Klopstock, Thomas

AU - Wittig, Ilka

AU - Prokisch, Holger

PY - 2021/3/15

Y1 - 2021/3/15

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Cell Line

KW - Child, Preschool

KW - Electron Transport Complex I/chemistry

KW - Female

KW - Gene Knockout Techniques

KW - Genes, Recessive

KW - HSP40 Heat-Shock Proteins/deficiency

KW - Homozygote

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation

KW - Optic Atrophy, Hereditary, Leber/genetics

KW - Pedigree

KW - Penetrance

KW - Phenotype

KW - Protein Subunits

KW - Reactive Oxygen Species/metabolism

KW - Young Adult

U2 - 10.1172/JCI138267

DO - 10.1172/JCI138267

M3 - SCORING: Journal article

C2 - 33465056

VL - 131

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 6

M1 - e138267

ER -