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.

Department of Developmental Neurosciences UCL Great Ormond Street Institute of Child Health London UK

Department of Neurology Asklepios Fachklinikum Stadtroda Stadtroda Germany

Department of Neurology Charles University Prague 1st Faculty of Medicine and General University Hospital Prague Prague Czech Republic

Department of Neurology Great Ormond Street Hospital London UK

Department of Neurology Klinikum rechts der Isar Technical University of Munich School of Medicine Munich Germany

Department of Neurology Medical University of Innsbruck Innsbruck Austria

Department of Neurology P J Safarik University Kosice Slovak Republic

Department of Neurology University Hospital of L Pasteur Kosice Slovak Republic

Department of Neurology University of Leipzig Leipzig Germany

Department of Pediatrics Carl Thiem Klinikum Cottbus Cottbus Germany

Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico Neurology Unit Milan Italy

Garvan Institute of Medical Research Darlinghurst New South Wales Australia

Institute of Experimental Dermatology and Institute of Cardiogenetics University of Lübeck Lübeck Germany

Institute of Human Genetics School of Medicine Technical University of Munich Munich Germany

Institute of Neurogenetics University of Lübeck Lübeck Germany

Institute of Neurogenomics Helmholtz Zentrum München Munich Germany

Ken and Ruth Davee Department of Neurology Simpson Querrey Center for Neurogenetics Northwestern University Feinberg School of Medicine Chicago Illinois USA

Lehrstuhl für Neurogenetik Technische Universität München Munich Germany

Movement Disorder and Neuromodulation Unit Department of Neurology Charité Universitätsmedizin Berlin Berlin Germany

Munich Cluster for Systems Neurology SyNergy Munich Germany

Translational Neurogenomics Group Molecular Medicine Laboratory and Neurology Department Concord Clinical School Concord Repatriation General Hospital The University of Sydney Sydney New South Wales Australia

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Combined genomics and proteomics unveils elusive variants and vast aetiologic heterogeneity in dystonia

CoPPIs algorithm: a tool to unravel protein cooperative strategies in pathophysiological conditions