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Harrer, P. ; Škorvánek, M.* ; Kittke, V. ; Dzinovic, I. ; Borngräber, F.* ; Thomsen, M.* ; Mandel, V. ; Svorenova, T.* ; Ostrozovičová, M.* ; Kulcsarová, K.* ; Berutti, R. ; Busch, H.* ; Ott, F.* ; Kopajtich, R. ; Prokisch, H. ; Kumar, K.R.* ; Mencacci, N.E.* ; Kurian, M.A.* ; Di Fonzo, A.* ; Boesch, S.* ; Kühn, A.A.* ; Blümlein, U.* ; Lohmann, K.* ; Haslinger, B.* ; Weise, D.* ; Jech, R.* ; Winkelmann, J. ; Zech, M.

Dystonia linked to EIF4A2 haploinsufficiency: A disorder of protein translation dysfunction.

Mov. Disord. 38, 1914-1924 (2023)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Eif4a2 ; Dystonia ; Loss-of-function Variants ; Translational Dysfunction ; Tremor; Developmental Delay; Variants; Eif2-alpha; Mutations; Genes
ISSN (print) / ISBN 0885-3185
e-ISSN 1531-8257
Zeitschrift Movement Disorders
Quellenangaben Band: 38, Heft: 10, Seiten: 1914-1924 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
Förderungen Charles University: Cooperation Program in Neuroscience
European Union-Next Generation EU
project PreDYT (PREdictive biomarkers in DYsTonia)
German Federal Ministry of Education and Research
European Joint Programme on Rare Diseases (EJP RD Joint Transnational Call 2022)
Helmholtz Zentrum Munchen (Munich, Germany)
in-house institutional funding from Technische Universität München (Munich, Germany)
Else Kroner-Fresenius-Stiftung