Journal Article

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

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

2021

Overview

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. Subunits of the Elongator complex have been implicated in several nervous system pathologies. Here, the authors identify ELP2 variants in six patients with neurodevelopmental anomalies and show in mouse models that these variants impact protein stability and the activity of the complex during brain development.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 14 / 59 / 631/136/1425 / 631/136/368/2430 / 64 / 64/60 / 96 / Animal models / Animals / Anomalies / Autism / Autism Spectrum Disorder - genetics / Autism Spectrum Disorder - metabolism / Autism Spectrum Disorder - physiopathology / Brain / Disease Models, Animal / Elongation / Epigenesis, Genetic / Grooming - physiology / Homeostasis / Humanities and Social Sciences / Humans / Intellectual disabilities / Intellectual Disability - genetics / Intellectual Disability - metabolism / Intellectual Disability - physiopathology / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Mice / Mice, Inbred C57BL / Mice, Inbred DBA / Mice, Knockout / Microencephaly / multidisciplinary / Mutation / Myelin / Nervous system / Neurodegeneration / Neurodevelopmental disorders / Neurodevelopmental Disorders - genetics / Neurodevelopmental Disorders - metabolism / Neurodevelopmental Disorders - physiopathology / Neurogenesis / Neuroimaging / Pathogenesis / Phenotype / Phenotypes / Proteins / Science / Science (multidisciplinary) / Sf9 Cells / Spodoptera / Substantia alba / Transcriptome - genetics / tRNA / tRNA Ala