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

Kojic, M; Gawda, T; Gaik, M; Begg, A; Salerno-Kochan, A; Kurniawan, ND; Jones, A; Drożdżyk, K; Kościelniak, A; Chramiec-Głąbik, A; Hediyeh-Zadeh, S; Kasherman, M; Shim, WJ; Sinniah, E; Genovesi, LA; Abrahamsen, RK; Fenger, CD; Madsen, CG; Cohen, JS; Fatemi, A; Stark, Z; Lunke, S; Lee, J; Hansen, JK; Boxill, MF; Keren, B; Marey, I; Saenz, MS; Brown, K; Alexander, SA; Mureev, S; Batzilla, A; Davis, MJ; Piper, M; Bod&#233;n, M; Burne, THJ; Palpant, NJ; M&#248;ller, RS; Glatt, S; Wainwright, BJ

Author(s): Kojic, M; Gawda, T; Gaik, M; Begg, A; Salerno-Kochan, A; Kurniawan, ND; Jones, A; Drożdżyk, K; Kościelniak, A; Chramiec-Głąbik, A; Hediyeh-Zadeh, S; Kasherman, M; Shim, WJ; Sinniah, E; Genovesi, LA; Abrahamsen, RK; Fenger, CD; Madsen, CG; Cohen, JS; Fatemi, A; Stark, Z; Lunke, S; Lee, J; Hansen, JK; Boxill, MF; Keren, B; Marey, I; Saenz, MS; Brown, K; Alexander, SA; Mureev, S; Batzilla, A; Davis, MJ; Piper, M; Bodén, M; Burne, THJ; Palpant, NJ; Møller, RS; Glatt, S; Wainwright, BJ;
Details: Publication Year 2021-05-11,Volume 12,Issue #1,Page 2678
Journal Title: Nature Communications
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.
Publisher: NPG
Research Division(s): Bioinformatics
PubMed ID: 33976153
Publisher's Version: https://doi.org/10.1038/s41467-021-22888-5
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-021-22888-5
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: Kojic M et al Nature Comms_2021.pdf - (12.16MB, application/pdf)

Creation Date: 2021-05-17 11:04:10

Last Modified: 2021-05-17 11:43:52