1. Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype
- Author
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Nyoman D. Kurniawan, Margarita Saenz, Melissa J. Davis, Anna Salerno-Kochan, Julie S. Cohen, Sebastian Glatt, Anna Kościelniak, Ali Fatemi, Mikael Bodén, Martin F. Boxill, Joy Lee, Woo Jun Shim, Nathan J. Palpant, Tomasz Gawda, Jonas K. Hansen, Katarzyna Drożdżyk, Alexander Begg, Rikke S. Møller, Michael Piper, Marija Kojic, Soroor Hediyeh-Zadeh, Thomas H. J. Burne, Brandon J. Wainwright, Kathleen Brown, Isabelle Marey, Sergey Mureev, Rannvá K. Abrahamsen, Enakshi Sinniah, Zornitza Stark, Laura A. Genovesi, Monika Gaik, Andrzej Chramiec-Głąbik, Suzanne Alexander, Alun Jones, Alina Batzilla, Christina Fenger, Camilla Gøbel Madsen, Maria Kasherman, Boris Keren, and Sebastian Lunke
- Subjects
0301 basic medicine ,Microcephaly ,TRNA modification ,Autism Spectrum Disorder ,Science ,General Physics and Astronomy ,Spodoptera ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,Intellectual Disability ,Intellectual disability ,Sf9 Cells ,medicine ,Animals ,Humans ,Mice, Knockout ,Mutation ,Multidisciplinary ,Neurodegeneration ,Intracellular Signaling Peptides and Proteins ,Translation (biology) ,General Chemistry ,medicine.disease ,Grooming ,Phenotype ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Mice, Inbred DBA ,Neurodevelopmental Disorders ,Autism spectrum disorder ,Transcriptome ,Neuroscience ,030217 neurology & neurosurgery - 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.
- Published
- 2021