TY  - JOUR
AU  - Peymani, Fatemeh
AU  - Ebihara, Tomohiro
AU  - Smirnov, Dmitrii
AU  - Kopajtich, Robert
AU  - Ando, Masahiro
AU  - Bertini, Enrico
AU  - Carrozzo, Rosalba
AU  - Diodato, Daria
AU  - Distelmaier, Felix
AU  - Fang, Fang
AU  - Ghezzi, Daniele
AU  - Hempel, Maja
AU  - Iwanicka-Pronicka, Katarzyna
AU  - Klopstock, Thomas
AU  - Stenton, Sarah L
AU  - Lamperti, Costanza
AU  - Liu, Zhimei
AU  - Murtazina, Aysylu
AU  - Okamoto, Yuji
AU  - Okazaki, Yasushi
AU  - Piekutowska-Abramczuk, Dorota
AU  - Rötig, Agnés
AU  - Ryzhkova, Oxana
AU  - Schlein, Christian
AU  - Shagina, Olga
AU  - Takashima, Hiroshi
AU  - Tsygankova, Polina
AU  - Zech, Michael
AU  - Meitinger, Thomas
AU  - Shimura, Masaru
AU  - Murayama, Kei
AU  - Prokisch, Holger
TI  - Pleiotropic effects of MORC2 derive from its epigenetic signature.
JO  - Brain
VL  - 149
IS  - 1
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2026-00054
SP  - 163 - 177
PY  - 2026
AB  - 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.
KW  - Humans
KW  - DNA Methylation: genetics
KW  - Epigenesis, Genetic: genetics
KW  - Male
KW  - Female
KW  - Genetic Pleiotropy: genetics
KW  - Transcription Factors: genetics
KW  - Phenotype
KW  - Mutation, Missense
KW  - CMT (Other)
KW  - Leigh syndrome (Other)
KW  - MORC2 (Other)
KW  - episignature (Other)
KW  - multi-omics (Other)
KW  - pleiotropy (Other)
KW  - Transcription Factors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40302207
C2  - pmc:PMC12782172
DO  - DOI:10.1093/brain/awaf159
UR  - https://pub.dzne.de/record/283158
ER  -