Functional divergence of the two Elongator subcomplexes during neurodevelopment

Autor: Monika Gaik, Marija Kojic, Megan R Stegeman, Tülay Öncü‐Öner, Anna Kościelniak, Alun Jones, Ahmed Mohamed, Pak Yan Stefanie Chau, Sazia Sharmin, Andrzej Chramiec‐Głąbik, Paulina Indyka, Michał Rawski, Anna Biela, Dominika Dobosz, Amanda Millar, Vann Chau, Aycan Ünalp, Michael Piper, Mark C Bellingham, Evan E Eichler, Deborah A Nickerson, Handan Güleryüz, Nour El Hana Abbassi, Konrad Jazgar, Melissa J Davis, Saadet Mercimek‐Andrews, Sultan Cingöz, Brandon J Wainwright, Sebastian Glatt
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 14, Iss 7, Pp 1-21 (2022)
Druh dokumentu: article
ISSN: 1757-4676
1757-4684
DOI: 10.15252/emmm.202115608
Popis: Abstract The highly conserved Elongator complex is a translational regulator that plays a critical role in neurodevelopment, neurological diseases, and brain tumors. Numerous clinically relevant variants have been reported in the catalytic Elp123 subcomplex, while no missense mutations in the accessory subcomplex Elp456 have been described. Here, we identify ELP4 and ELP6 variants in patients with developmental delay, epilepsy, intellectual disability, and motor dysfunction. We determine the structures of human and murine Elp456 subcomplexes and locate the mutated residues. We show that patient‐derived mutations in Elp456 affect the tRNA modification activity of Elongator in vitro as well as in human and murine cells. Modeling the pathogenic variants in mice recapitulates the clinical features of the patients and reveals neuropathology that differs from the one caused by previously characterized Elp123 mutations. Our study demonstrates a direct correlation between Elp4 and Elp6 mutations, reduced Elongator activity, and neurological defects. Foremost, our data indicate previously unrecognized differences of the Elp123 and Elp456 subcomplexes for individual tRNA species, in different cell types and in different key steps during the neurodevelopment of higher organisms.
Databáze: Directory of Open Access Journals
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