Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype. productsSearch results for: Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype.
#33976153 
2021/05/11
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Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype.
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.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
