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

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 () and Brandon J. Wainwright ()
Additional contact information
Marija Kojic: The University of Queensland
Tomasz Gawda: Jagiellonian University
Monika Gaik: Jagiellonian University
Alexander Begg: The University of Queensland
Anna Salerno-Kochan: Jagiellonian University
Nyoman D. Kurniawan: The University of Queensland
Alun Jones: The University of Queensland
Katarzyna Drożdżyk: Jagiellonian University
Anna Kościelniak: Jagiellonian University
Andrzej Chramiec-Głąbik: Jagiellonian University
Soroor Hediyeh-Zadeh: Walter and Eliza Hall Institute of Medical Research
Maria Kasherman: The University of Queensland
Woo Jun Shim: The University of Queensland
Enakshi Sinniah: The University of Queensland
Laura A. Genovesi: The University of Queensland
Rannvá K. Abrahamsen: Danish Epilepsy Centre
Christina D. Fenger: Danish Epilepsy Centre
Camilla G. Madsen: Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital
Julie S. Cohen: Division of Neurogenetics, Kennedy Krieger Institute
Ali Fatemi: Division of Neurogenetics, Kennedy Krieger Institute
Zornitza Stark: The University of Melbourne
Sebastian Lunke: Murdoch Children’s Research Institute
Joy Lee: The University of Melbourne
Jonas K. Hansen: Regional Hospital Viborg
Martin F. Boxill: Regional Hospital Viborg
Boris Keren: Pitié-Salpêtrière Hospital, AP-HP
Isabelle Marey: Pitié-Salpêtrière Hospital, AP-HP
Margarita S. Saenz: The University of Colorado Anschutz, Children’s Hospital Colorado
Kathleen Brown: The University of Colorado Anschutz, Children’s Hospital Colorado
Suzanne A. Alexander: The University of Queensland
Sergey Mureev: Queensland University of Technology
Alina Batzilla: The University of Queensland
Melissa J. Davis: Walter and Eliza Hall Institute of Medical Research
Michael Piper: The University of Queensland
Mikael Bodén: The University of Queensland
Thomas H. J. Burne: The University of Queensland
Nathan J. Palpant: The University of Queensland
Rikke S. Møller: Danish Epilepsy Centre
Sebastian Glatt: Jagiellonian University
Brandon J. Wainwright: The University of Queensland

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22888-5

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DOI: 10.1038/s41467-021-22888-5

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