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Peymani, F. ; Ebihara, T. ; Smirnov, D. ; Kopajtich, R. ; Ando, M.* ; Bertini, E.* ; Carrozzo, R.* ; Diodato, D.* ; Distelmaier, F.* ; Fang, F.* ; Ghezzi, D.* ; Hempel, M.* ; Iwanicka-Pronicka, K.* ; Klopstock, T.* ; Stenton, S. ; Lamperti, C.* ; Liu, Z.* ; Murtazina, A.* ; Okamoto, Y.* ; Okazaki, Y.* ; Piekutowska-Abramczuk, D.* ; Rötig, A.* ; Ryzhkova, O.* ; Schlein, C.* ; Shagina, O.* ; Takashima, H.* ; Tsygankova, P.G.* ; Zech, M. ; Meitinger, T.* ; Shimura, M. ; Murayama, K.* ; Prokisch, H.

Pleiotropic effects of MORC2 derive from its epigenetic signature.

Brain:awaf159 (2025)
Verlagsversion Postprint DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Heterozygous missense mutations in MORC2 have been implicated in various clinical entities, ranging from early-onset neurodevelopmental disorders to late-onset neuropathies. The mechanism underlying the phenotypic heterogeneity and pleiotropic effects of MORC2 has remained elusive. Here, we analyzed blood and fibroblast DNA methylation, transcriptomes, proteomes, and phenotypes of 53 MORC2 patients. We identified a MORC2-specific DNA methylation episignature that is universal across all MORC2-associated phenotypes and conserved across different tissues. The MORC2 episignature consists mainly of DNA hypermethylation in promoter regions, leading to transcriptional repression of target genes resulting in a MORC2-specific RNA signature. Concomitant downregulation of three disease-associated genes -ERCC8, NDUFAF2, and FKTN- at different levels mirrors the variable biochemical defects and clinical manifestations observed in MORC2 patients. Silencing of NDUFAF2 accounts for the Leigh syndrome manifestation, whereas dysmorphic features are due to the repression of ERCC8. Overall, we showed that pathogenic MORC2 variants cause specific episignature, whereby methylation level variability and its repression impact on target genes explains the pleiotropy and predicts phenotypic heterogeneity in MORC2-related disorders. We predict that epigenetic variation may underlie pleiotropy in other Mendelian disorders.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cmt ; Leigh Syndrome ; Morc2 ; Episignature ; Multi-omics ; Pleiotropy; Protein Chaperone; Mutations
ISSN (print) / ISBN 0006-8950
e-ISSN 1460-2156
Zeitschrift Brain: A Journal of Neurology
Quellenangaben Band: , Heft: , Seiten: , Artikelnummer: awaf159 Supplement: ,
Verlag Oxford University Press
Verlagsort Great Clarendon St, Oxford Ox2 6dp, England
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
Förderungen Elterninitiative Kinderkrebsklinik e.V.
Japan Agency for Medical Research and Development
DZKJ
Ministry of Health, Labor and Welfare
BMBF
Else Krner-Fresenius-Stiftung
Research Committee for Ataxic Disease
Institute for Advanced Study
Bavarian Ministry of Health, Care and Prevention
Technical University of Munich
Japan Society for the Promotion of Science
Horizon 2020
German Research Foundation