1. Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype.
- Author
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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, and Wainwright BJ
- Subjects
- Animals, Autism Spectrum Disorder metabolism, Autism Spectrum Disorder physiopathology, Disease Models, Animal, Epigenesis, Genetic, Grooming physiology, Humans, Intellectual Disability metabolism, Intellectual Disability physiopathology, Intracellular Signaling Peptides and Proteins metabolism, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, Neurodevelopmental Disorders metabolism, Neurodevelopmental Disorders physiopathology, Phenotype, Sf9 Cells, Spodoptera, Mice, Autism Spectrum Disorder genetics, Intellectual Disability genetics, Intracellular Signaling Peptides and Proteins genetics, Mutation, Neurodevelopmental Disorders genetics, Transcriptome genetics
- 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
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