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@ARTICLE{Peymani:283158,
      author       = {Peymani, Fatemeh and Ebihara, Tomohiro and Smirnov, Dmitrii
                      and Kopajtich, Robert and Ando, Masahiro and Bertini, Enrico
                      and Carrozzo, Rosalba and Diodato, Daria and Distelmaier,
                      Felix and Fang, Fang and Ghezzi, Daniele and Hempel, Maja
                      and Iwanicka-Pronicka, Katarzyna and Klopstock, Thomas and
                      Stenton, Sarah L and Lamperti, Costanza and Liu, Zhimei and
                      Murtazina, Aysylu and Okamoto, Yuji and Okazaki, Yasushi and
                      Piekutowska-Abramczuk, Dorota and Rötig, Agnés and
                      Ryzhkova, Oxana and Schlein, Christian and Shagina, Olga and
                      Takashima, Hiroshi and Tsygankova, Polina and Zech, Michael
                      and Meitinger, Thomas and Shimura, Masaru and Murayama, Kei
                      and Prokisch, Holger},
      title        = {{P}leiotropic effects of {MORC}2 derive from its epigenetic
                      signature.},
      journal      = {Brain},
      volume       = {149},
      number       = {1},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2026-00054},
      pages        = {163 - 177},
      year         = {2026},
      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.},
      keywords     = {Humans / DNA Methylation: genetics / Epigenesis, Genetic:
                      genetics / Male / Female / Genetic Pleiotropy: genetics /
                      Transcription Factors: genetics / Phenotype / Mutation,
                      Missense / CMT (Other) / Leigh syndrome (Other) / MORC2
                      (Other) / episignature (Other) / multi-omics (Other) /
                      pleiotropy (Other) / Transcription Factors (NLM Chemicals)},
      cin          = {Clinical Research (Munich)},
      ddc          = {610},
      cid          = {I:(DE-2719)1111015},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40302207},
      pmc          = {pmc:PMC12782172},
      doi          = {10.1093/brain/awaf159},
      url          = {https://pub.dzne.de/record/283158},
}