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Kojic, Marija; Gawda, Tomasz; Gaik, Monika; Begg, Alexander; Salerno-Kochan, Anna; Kurniawan, Nyoman D.; Jones, Alun; Drożdżyk, Katarzyna; Kościelniak, Anna; Chramiec-Głąbik, Andrzej; Hediyeh-Zadeh, Soroor; Kasherman, Maria; Shim, Woo Jun; Sinniah, Enakshi; Genovesi, Laura A.; Abrahamsen, Rannvá K.; Fenger, Christina D.; Madsen, Camilla G.; Cohen, Julie S.; Fatemi, Ali; Stark, Zornitza; Lunke, Sebastian; Lee, Joy; Hansen, Jonas K.; [...]

Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype

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  • Medientyp: E-Artikel
  • Titel: Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype
  • Beteiligte: Kojic, Marija; Gawda, Tomasz; Gaik, Monika; Begg, Alexander; Salerno-Kochan, Anna; Kurniawan, Nyoman D.; Jones, Alun; Drożdżyk, Katarzyna; Kościelniak, Anna; Chramiec-Głąbik, Andrzej; Hediyeh-Zadeh, Soroor; Kasherman, Maria; Shim, Woo Jun; Sinniah, Enakshi; Genovesi, Laura A.; Abrahamsen, Rannvá K.; Fenger, Christina D.; Madsen, Camilla G.; Cohen, Julie S.; Fatemi, Ali; Stark, Zornitza; Lunke, Sebastian; Lee, Joy; Hansen, Jonas K.; [...]
  • Erschienen: Springer Science and Business Media LLC, 2021
  • Erschienen in: Nature Communications, 12 (2021) 1
  • Sprache: Englisch
  • DOI: 10.1038/s41467-021-22888-5
  • ISSN: 2041-1723
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the <jats:italic>Elp2</jats:italic> mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis leading to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and define Elp2 as a key regulator of brain development.</jats:p>
  • Zugangsstatus: Freier Zugang