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Dystonia Linked to EIF4A2 Haploinsufficiency: A Disorder of Protein Translation Dysfunction
Authors
Riccardo Berutti
Ulrike Bluemlein
+26 more
Sylvia Boesch
Friederike Borngraeber
Hauke Busch
Alessio Di Fonzo
Ivana Dzinovic
Philip Harrer
Bernhard Haslinger
Robert Jech
Volker Kittke
Robert Kopajtich
Andrea A Kuehn
Kristina Kulcsarova
Kishore R Kumar
Manju A Kurian
Katja Lohmann
Vanessa Mandel
Niccolo E Mencacci
Miriam Ostrozovicova
Fabian Ott
Holger Prokisch
Matej Skorvanek
Tatiana Svorenova
Mirja Thomsen
David Weise
Juliane Winkelmann
Michael Zech
Publication date
23 July 2023
Publisher
'Royal College of Obstetricians & Gynaecologists (RCOG)'
Abstract
Background: Protein synthesis is a tightly controlled process, involving a host of translation-initiation factors and microRNA-associated repressors. Variants in the translational regulator EIF2AK2 were first linked to neurodevelopmental-delay phenotypes, followed by their implication in dystonia. Recently, de novo variants in EIF4A2, encoding eukaryotic translation initiation factor 4A isoform 2 (eIF4A2), have been described in pediatric cases with developmental delay and intellectual disability. Objective: We sought to characterize the role of EIF4A2 variants in dystonic conditions. Methods: We undertook an unbiased search for likely deleterious variants in mutation-constrained genes among 1100 families studied with dystonia. Independent cohorts were screened for EIF4A2 variants. Western blotting and immunocytochemical studies were performed in patient-derived fibroblasts. Results: We report the discovery of a novel heterozygous EIF4A2 frameshift deletion (c.896_897del) in seven patients from two unrelated families. The disease was characterized by adolescence- to adulthood-onset dystonia with tremor. In patient-derived fibroblasts, eIF4A2 production amounted to only 50% of the normal quantity. Reduction of eIF4A2 was associated with abnormally increased levels of IMP1, a target of Ccr4-Not, the complex that interacts with eIF4A2 to mediate microRNA-dependent translational repression. By complementing the analyses with fibroblasts bearing EIF4A2 biallelic mutations, we established a correlation between IMP1 expression alterations and eIF4A2 functional dosage. Moreover, eIF4A2 and Ccr4-Not displayed significantly diminished colocalization in dystonia patient cells. Review of international databases identified EIF4A2 deletion variants (c.470_472del, c.1144_1145del) in another two dystonia-affected pedigrees. Conclusions: Our findings demonstrate that EIF4A2 haploinsufficiency underlies a previously unrecognized dominant dystonia-tremor syndrome. The data imply that translational deregulation is more broadly linked to both early neurodevelopmental phenotypes and later-onset dystonic conditions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
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Last time updated on 28/08/2023