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Hvidovre Hospital - en del af Københavns Universitetshospital

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

Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review


  • Marija Kojic
  • Tomasz Gawda
  • Monika Gaik
  • Alexander Begg
  • Anna Salerno-Kochan
  • Nyoman D Kurniawan
  • Alun Jones
  • Katarzyna Drożdżyk
  • Anna Kościelniak
  • Andrzej Chramiec-Głąbik
  • Soroor Hediyeh-Zadeh
  • Maria Kasherman
  • Woo Jun Shim
  • Enakshi Sinniah
  • Laura A Genovesi
  • Rannvá K Abrahamsen
  • Christina D Fenger
  • Camilla G Madsen
  • Julie S Cohen
  • Ali Fatemi
  • Zornitza Stark
  • Sebastian Lunke
  • Joy Lee
  • Jonas K Hansen
  • Martin F Boxill
  • Boris Keren
  • Isabelle Marey
  • Margarita S Saenz
  • Kathleen Brown
  • Suzanne A Alexander
  • Sergey Mureev
  • Alina Batzilla
  • Melissa J Davis
  • Michael Piper
  • Mikael Bodén
  • Thomas H J Burne
  • Nathan J Palpant
  • Rikke S Møller
  • Sebastian Glatt
  • Brandon J Wainwright
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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 Elp2 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.

TidsskriftNature Communications
Udgave nummer1
Sider (fra-til)1-18
Antal sider18
StatusUdgivet - 11 maj 2021

Bibliografisk note

Funding Information:
We thank all members of the Wainwright and Glatt laboratories for discussion and suggestions. The authors acknowledge Jérémy Potriquet from the AB Sciex company, Brisbane, Australia, for his assistance with proteome data quantification and analysis. This work was supported by the First Team Grant (FirstTEAM/2016-1/2; A.C.G. and S.G.) from the Foundation for Polish Science. In addition, we thank the MCB structural biology core facility (supported by the TEAM TECH CORE FACILITY/2017-4/6 grant from Foundation for Polish Science) for providing computational resources and support. We acknowledge the supports from the Queensland NMR Network and the National Imaging Facility (a National Collaborative Research Infrastructure Strategy capability) for the operation of 16.4 T MRI at the Centre for Advanced Imaging, the University of Queensland. Patient 6 (refer to Supplementary Table 1) was tested through the Acute Care Flagship of the Australian Genomics Health Alliance, supported by grants from the Royal Children’s Hospital Foundation (2017-906) and the National Health and Medical Research Council (GNT1113531). The open-access publication of this article was funded by the BioS Priority Research Area under the program Excellence Initiative – Research University at the Jagiellonian University in Krakow.

ID: 65653720