Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype.
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ABSTRACT:
SUBMITTER: Kojic M
PROVIDER: S-EPMC8113450 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
Publications
Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype.
Kojic Marija M Gawda Tomasz T Gaik Monika M Begg Alexander A Salerno-Kochan Anna A Kurniawan Nyoman D ND Jones Alun A Drożdżyk Katarzyna K Kościelniak Anna A Chramiec-Głąbik Andrzej A Hediyeh-Zadeh Soroor S Kasherman Maria M Shim Woo Jun WJ Sinniah Enakshi E Genovesi Laura A LA Abrahamsen Rannvá K RK Fenger Christina D CD Madsen Camilla G CG Cohen Julie S JS Fatemi Ali A Stark Zornitza Z Lunke Sebastian S Lee Joy J Hansen Jonas K JK Boxill Martin F MF Keren Boris B Marey Isabelle I Saenz Margarita S MS Brown Kathleen K Alexander Suzanne A SA Mureev Sergey S Batzilla Alina A Davis Melissa J MJ Piper Michael M Bodén Mikael M Burne Thomas H J THJ Palpant Nathan J NJ Møller Rikke S RS Glatt Sebastian S Wainwright Brandon J BJ
Nature communications 20210511 1
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 tractogra ...[more]
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Project description:Neurodevelopmental disorders have a variety of aetiologies and most often these are complex genomic traits involving numerous mutations. 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 identified biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulated 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 by reducing expression of the genes that guide cell cycle and translation, and up-regulating protein degradation in neurons and oligodendroglia. This leads 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 defines Elp2 as a key regulator of brain development.
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