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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)

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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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