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

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

doi:10.1038/s41467-021-22888-5

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.

Highlights

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
Following from our data that hElp2H206R and hElp2R462W have a detrimental effect on the stability and activity of the Elongator complex in vitro, we further investigated the consequence of these mutations on tRNA modification levels in the Elp2H206R and Elp2H206R/R464W mice
Next-generation sequencing studies have suggested rare ELP2 variants to be associated with ID19–21, which led us to identify a number of individuals with ELP2 variants and to define the role of this gene in the neurodevelopment and associated pathologies

Summary

Introduction

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. ID is characterized by severe impairments in cognition and adaptive daily life skills functioning[4] It commonly occurs in combination with global developmental delay, autism spectrum disorder (ASD), epilepsy, and ataxia[4,5,6]. A number of cell activities have been assigned to the complex[29], but it is widely accepted that its main function is the formation of 5‐carboxymethyl‐uridine (cm5U) in the wobble base (U34) position of 12 mammalian tRNAs30,31 These U34 modifications tune ribosomal speed during translational elongation, affecting tRNA binding, recognition, rejection, decoding and translocation. Our comprehensive study of the clinically relevant ELP2 mutations reveals the role of epitranscriptomic processes in brain development and homeostasis which, when perturbed, lead to profound CNS defects in both humans and model systems

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Conclusion