Dystonia Linked to EIF4A2 Haploinsufficiency: A Disorder of Protein Translation Dysfunction

Media type: E-Article
Title: Dystonia Linked to EIF4A2 Haploinsufficiency: A Disorder of Protein Translation Dysfunction
Contributor: Harrer, Philip; Škorvánek, Matej; Kittke, Volker; Dzinovic, Ivana; Borngräber, Friederike; Thomsen, Mirja; Mandel, Vanessa; Svorenova, Tatiana; Ostrozovicova, Miriam; Kulcsarova, Kristina; Berutti, Riccardo; Busch, Hauke; Ott, Fabian; Kopajtich, Robert; Prokisch, Holger; Kumar, Kishore R.; Mencacci, Niccolo E.; Kurian, Manju A.; Di Fonzo, Alessio; Boesch, Sylvia; Kühn, Andrea A.; Blümlein, Ulrike; Lohmann, Katja; Haslinger, Bernhard; [...]
imprint: Wiley, 2023
Published in: Movement Disorders
Language: English
DOI: 10.1002/mds.29562
ISSN: 0885-3185; 1531-8257
Keywords: Neurology (clinical) ; Neurology
Origination:
Footnote:
Description: <jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Protein synthesis is a tightly controlled process, involving a host of translation‐initiation factors and microRNA‐associated repressors. Variants in the translational regulator <jats:italic>EIF2AK2</jats:italic> were first linked to neurodevelopmental‐delay phenotypes, followed by their implication in dystonia. Recently, de novo variants in <jats:italic>EIF4A2</jats:italic>, encoding eukaryotic translation initiation factor 4A isoform 2 (eIF4A2), have been described in pediatric cases with developmental delay and intellectual disability.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>We sought to characterize the role of <jats:italic>EIF4A2</jats:italic> variants in dystonic conditions.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We undertook an unbiased search for likely deleterious variants in mutation‐constrained genes among 1100 families studied with dystonia. Independent cohorts were screened for <jats:italic>EIF4A2</jats:italic> variants. Western blotting and immunocytochemical studies were performed in patient‐derived fibroblasts.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We report the discovery of a novel heterozygous <jats:italic>EIF4A2</jats:italic> 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 <jats:italic>EIF4A2</jats:italic> 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 <jats:italic>EIF4A2</jats:italic> deletion variants (c.470_472del, c.1144_1145del) in another two dystonia‐affected pedigrees.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Our findings demonstrate that <jats:italic>EIF4A2</jats:italic> 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. <jats:italic>Movement Disorders</jats:italic> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.</jats:p></jats:sec>

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