Journal Article

DZNE-2021-01184

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Impaired complex I repair causes recessive Leber's hereditary optic neuropathy.

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.DZNE* ; Wittig, I. ; Prokisch, H.

2021
ASCJ Ann Arbor, Mich.

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Please use a persistent id in citations: doi:10.1172/JCI138267

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.

Keyword(s): Adolescent (MeSH) ; Adult (MeSH) ; Cell Line (MeSH) ; Child, Preschool (MeSH) ; Electron Transport Complex I: chemistry (MeSH) ; Electron Transport Complex I: metabolism (MeSH) ; Female (MeSH) ; Gene Knockout Techniques (MeSH) ; Genes, Recessive (MeSH) ; HSP40 Heat-Shock Proteins: deficiency (MeSH) ; HSP40 Heat-Shock Proteins: genetics (MeSH) ; HSP40 Heat-Shock Proteins: metabolism (MeSH) ; Homozygote (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Middle Aged (MeSH) ; Mutation (MeSH) ; Optic Atrophy, Hereditary, Leber: genetics (MeSH) ; Optic Atrophy, Hereditary, Leber: metabolism (MeSH) ; Pedigree (MeSH) ; Penetrance (MeSH) ; Phenotype (MeSH) ; Protein Subunits (MeSH) ; Reactive Oxygen Species: metabolism (MeSH) ; Young Adult (MeSH) ; Genetic diseases ; Genetics ; Neuroscience

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Contributing Institute(s):

1. Coordinator of Clinical Parkinson Research (AG Höglinger 2)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2021

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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