PuSH - Publication Server of Helmholtz Zentrum München: Pleiotropic effects of <em>MORC2</em> derive from its epigenetic signature.

Information

Clues to quality of journals

Open Access Policy of Helmholtz Association 2016

CC Licencences

Publication Metrics

Navigation

Home

Deutsch

Research

Advanced Search

Browse by ...

... HMGU-Authors/Consortia

... Organizational Structure

... Journal

... Publication Type

... Research Data

... Arbeitsgruppen

... Publication Year

Publication overview

Statistics

Statistics (last 5 years)

OA Publications

Publish

Submit Publication

Import publication from...

...EVA

Report missing publication

Highlights

Support & Contact

Contact persons

Help

Data protection

Helmholtz Open Science

JANE Journal Estimator

SHERPA/RoMEO

DOAJ

Export:

Text

Endnote (RIS) BIB

BibTeX

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)

Postprint

DOI

PMC

	Open Access Green

Abstract
Metrics
Extra information

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.

Impact Factor

Scopus SNIP

Altmetric

11.700

0.000