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000283158 1001_ $$aPeymani, Fatemeh$$b0
000283158 245__ $$aPleiotropic effects of MORC2 derive from its epigenetic signature.
000283158 260__ $$aOxford$$bOxford Univ. Press$$c2026
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000283158 520__ $$aHeterozygous missense mutations in MORC2 have been implicated in various clinical entities, ranging from early-onset neurodevelopmental disorders to late-onset neuropathies. The mechanism underlying the phenotypic heterogeneity and pleiotropic effects of MORC2 has remained elusive. Here, we analysed blood and fibroblast DNA methylation, transcriptomes, proteomes and phenotypes of 53 MORC2 patients. We identified a MORC2-specific DNA methylation episignature that is universal across all MORC2-associated phenotypes and conserved across different tissues. The MORC2 episignature consists mainly of DNA hypermethylation in promoter regions, leading to transcriptional repression of target genes resulting in a MORC2-specific RNA signature. Concomitant downregulation of three disease-associated genes-ERCC8, NDUFAF2 and FKTN-at different levels mirrors the variable biochemical defects and clinical manifestations observed in MORC2 patients. Silencing of NDUFAF2 accounts for the Leigh syndrome manifestation, whereas dysmorphic features are due to the repression of ERCC8. Overall, we showed that pathogenic MORC2 variants cause specific episignature, whereby methylation level variability and its repression impact on target genes explains the pleiotropy and predicts phenotypic heterogeneity in MORC2-related disorders. We predict that epigenetic variation may underlie pleiotropy in other Mendelian disorders.
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000283158 650_7 $$2Other$$aCMT
000283158 650_7 $$2Other$$aLeigh syndrome
000283158 650_7 $$2Other$$aMORC2
000283158 650_7 $$2Other$$aepisignature
000283158 650_7 $$2Other$$amulti-omics
000283158 650_7 $$2Other$$apleiotropy
000283158 650_7 $$2NLM Chemicals$$aTranscription Factors
000283158 650_2 $$2MeSH$$aHumans
000283158 650_2 $$2MeSH$$aDNA Methylation: genetics
000283158 650_2 $$2MeSH$$aEpigenesis, Genetic: genetics
000283158 650_2 $$2MeSH$$aMale
000283158 650_2 $$2MeSH$$aFemale
000283158 650_2 $$2MeSH$$aGenetic Pleiotropy: genetics
000283158 650_2 $$2MeSH$$aTranscription Factors: genetics
000283158 650_2 $$2MeSH$$aPhenotype
000283158 650_2 $$2MeSH$$aMutation, Missense
000283158 7001_ $$aEbihara, Tomohiro$$b1
000283158 7001_ $$aSmirnov, Dmitrii$$b2
000283158 7001_ $$aKopajtich, Robert$$b3
000283158 7001_ $$aAndo, Masahiro$$b4
000283158 7001_ $$00000-0001-9276-4590$$aBertini, Enrico$$b5
000283158 7001_ $$00000-0002-3327-4054$$aCarrozzo, Rosalba$$b6
000283158 7001_ $$aDiodato, Daria$$b7
000283158 7001_ $$00000-0001-8460-3738$$aDistelmaier, Felix$$b8
000283158 7001_ $$aFang, Fang$$b9
000283158 7001_ $$00000-0002-6564-3766$$aGhezzi, Daniele$$b10
000283158 7001_ $$aHempel, Maja$$b11
000283158 7001_ $$aIwanicka-Pronicka, Katarzyna$$b12
000283158 7001_ $$0P:(DE-2719)2810704$$aKlopstock, Thomas$$b13$$udzne
000283158 7001_ $$aStenton, Sarah L$$b14
000283158 7001_ $$aLamperti, Costanza$$b15
000283158 7001_ $$aLiu, Zhimei$$b16
000283158 7001_ $$aMurtazina, Aysylu$$b17
000283158 7001_ $$aOkamoto, Yuji$$b18
000283158 7001_ $$aOkazaki, Yasushi$$b19
000283158 7001_ $$aPiekutowska-Abramczuk, Dorota$$b20
000283158 7001_ $$00000-0003-0589-0703$$aRötig, Agnés$$b21
000283158 7001_ $$aRyzhkova, Oxana$$b22
000283158 7001_ $$aSchlein, Christian$$b23
000283158 7001_ $$aShagina, Olga$$b24
000283158 7001_ $$aTakashima, Hiroshi$$b25
000283158 7001_ $$aTsygankova, Polina$$b26
000283158 7001_ $$aZech, Michael$$b27
000283158 7001_ $$aMeitinger, Thomas$$b28
000283158 7001_ $$aShimura, Masaru$$b29
000283158 7001_ $$00000-0002-3923-8636$$aMurayama, Kei$$b30
000283158 7001_ $$aProkisch, Holger$$b31
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