Journal Article

DZNE-2026-00054

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Pleiotropic effects of MORC2 derive from its epigenetic signature.

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.DZNE* ; Stenton, S. L. ; 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. ; Zech, M. ; Meitinger, T. ; Shimura, M. ; Murayama, K. ; Prokisch, H.

2026
Oxford Univ. Press Oxford

This record in other databases:    

Please use a persistent id in citations: doi:10.1093/brain/awaf159

Abstract: 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 analysed 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.

Keyword(s): Humans (MeSH) ; DNA Methylation: genetics (MeSH) ; Epigenesis, Genetic: genetics (MeSH) ; Male (MeSH) ; Female (MeSH) ; Genetic Pleiotropy: genetics (MeSH) ; Transcription Factors: genetics (MeSH) ; Phenotype (MeSH) ; Mutation, Missense (MeSH) ; CMT ; Leigh syndrome ; MORC2 ; episignature ; multi-omics ; pleiotropy ; Transcription Factors

---

Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))

Research Program(s):

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

---

Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---