EMBO Molecular Medicine (Jul 2022)
Functional divergence of the two Elongator subcomplexes during neurodevelopment
- 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
Affiliations
- Monika Gaik
- Malopolska Centre of Biotechnology Jagiellonian University Krakow Poland
- Marija Kojic
- The University of Queensland Diamantina Institute Faculty of Medicine The University of Queensland Woolloongabba QLD Australia
- Megan R Stegeman
- The University of Queensland Diamantina Institute Faculty of Medicine The University of Queensland Woolloongabba QLD Australia
- Tülay Öncü‐Öner
- Department of Medical Biology and Genetics Faculty of Medicine Dokuz Eylül University İzmir Turkey
- Anna Kościelniak
- Malopolska Centre of Biotechnology Jagiellonian University Krakow Poland
- Alun Jones
- Institute for Molecular Bioscience The University of Queensland Brisbane QLD Australia
- Ahmed Mohamed
- Bioinformatics Division The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
- Pak Yan Stefanie Chau
- School of Biomedical Sciences The University of Queensland Brisbane QLD Australia
- Sazia Sharmin
- School of Biomedical Sciences The University of Queensland Brisbane QLD Australia
- Andrzej Chramiec‐Głąbik
- Malopolska Centre of Biotechnology Jagiellonian University Krakow Poland
- Paulina Indyka
- Malopolska Centre of Biotechnology Jagiellonian University Krakow Poland
- Michał Rawski
- Malopolska Centre of Biotechnology Jagiellonian University Krakow Poland
- Anna Biela
- Malopolska Centre of Biotechnology Jagiellonian University Krakow Poland
- Dominika Dobosz
- Malopolska Centre of Biotechnology Jagiellonian University Krakow Poland
- Amanda Millar
- The University of Queensland Diamantina Institute Faculty of Medicine The University of Queensland Woolloongabba QLD Australia
- Vann Chau
- Department of Paediatrics (Neurology) The Hospital for Sick Children and University of Toronto Toronto ON Canada
- Aycan Ünalp
- Department of Pediatric Neurology Dr. Behçet Uz Children's Hospital İzmir Turkey
- Michael Piper
- School of Biomedical Sciences The University of Queensland Brisbane QLD Australia
- Mark C Bellingham
- School of Biomedical Sciences The University of Queensland Brisbane QLD Australia
- Evan E Eichler
- Department of Genome Sciences University of Washington School of Medicine Seattle WA USA
- Deborah A Nickerson
- Department of Genome Sciences University of Washington School of Medicine Seattle WA USA
- Handan Güleryüz
- Department of Pediatric Radiology School of Medicine Dokuz Eylül University İzmir Turkey
- Nour El Hana Abbassi
- Malopolska Centre of Biotechnology Jagiellonian University Krakow Poland
- Konrad Jazgar
- Malopolska Centre of Biotechnology Jagiellonian University Krakow Poland
- Melissa J Davis
- The University of Queensland Diamantina Institute Faculty of Medicine The University of Queensland Woolloongabba QLD Australia
- Saadet Mercimek‐Andrews
- The Hospital for Sick Children Toronto ON Canada
- Sultan Cingöz
- Department of Medical Biology and Genetics Faculty of Medicine Dokuz Eylül University İzmir Turkey
- Brandon J Wainwright
- The University of Queensland Diamantina Institute Faculty of Medicine The University of Queensland Woolloongabba QLD Australia
- Sebastian Glatt
- Malopolska Centre of Biotechnology Jagiellonian University Krakow Poland
- DOI
- https://doi.org/10.15252/emmm.202115608
- Journal volume & issue
-
Vol. 14,
no. 7
pp. n/a – n/a
Abstract
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.
Keywords