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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1914-1924 |
| Number of pages | 11 |
| Journal | Movement Disorders |
| Volume | 38 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2023 |
Funding
This study was supported by a research grant from the Else Kröner-Fresenius-Stiftung, as well as by in-house institutional funding from Technische Universität München (Munich, Germany) and Helmholtz Zentrum München (Munich, Germany). J.W. and M.Z. received research support from the German Research Foundation (DFG 458949627; WI 1820/14-1; ZE 1213/2-1). We acknowledge grant support from the European Joint Programme on Rare Diseases (EJP RD Joint Transnational Call 2022) and the German Federal Ministry of Education and Research (BMBF, Bonn, Germany), awarded to the project PreDYT (PREdictive biomarkers in DYsTonia, 01GM2302). This work was also supported by the National Institute for Neurological Research, Czech Republic, Programme EXCELES, ID Project LX22NPO5107, funded by the European Union—Next Generation EU and also by the Charles University: Cooperation Program in Neuroscience. K.L. received research support from the German Research Foundation (LO 1555/10-1). R.K. and H.P. acknowledge grant support from the BMBF awarded to the German Network for Mitochondrial Disorders (mitoNET, 01GM1906A). We are deeply indebted to the affected individuals and their families for their participation in this study. We are grateful to Annette Feuchtinger and Ulrike Buchholz (Core Facility Pathology and Tissue Analytics, Helmholtz Center Munich, Munich, Germany) for their excellent support with analyses of proximity ligation assays. We gratefully thank Monika Zimmermann and Celestine Dutta (Institute of Neurogenomics, Helmholtz Center Munich) for their generous contribution with immunoblotting analyses. We further thank Frauke Hinrichs (Institute of Neurogenetics, University of Lübeck) for technical support. Open Access funding enabled and organized by Projekt DEAL. This study was supported by a research grant from the Else Kröner‐Fresenius‐Stiftung, as well as by in‐house institutional funding from Technische Universität München (Munich, Germany) and Helmholtz Zentrum München (Munich, Germany). J.W. and M.Z. received research support from the German Research Foundation (DFG 458949627; WI 1820/14‐1; ZE 1213/2‐1). We acknowledge grant support from the European Joint Programme on Rare Diseases (EJP RD Joint Transnational Call 2022) and the German Federal Ministry of Education and Research (BMBF, Bonn, Germany), awarded to the project PreDYT (PREdictive biomarkers in DYsTonia, 01GM2302). This work was also supported by the National Institute for Neurological Research, Czech Republic, Programme EXCELES, ID Project LX22NPO5107, funded by the European Union—Next Generation EU and also by the Charles University: Cooperation Program in Neuroscience. K.L. received research support from the German Research Foundation (LO 1555/10‐1). R.K. and H.P. acknowledge grant support from the BMBF awarded to the German Network for Mitochondrial Disorders (mitoNET, 01GM1906A). We are deeply indebted to the affected individuals and their families for their participation in this study. We are grateful to Annette Feuchtinger and Ulrike Buchholz (Core Facility Pathology and Tissue Analytics, Helmholtz Center Munich, Munich, Germany) for their excellent support with analyses of proximity ligation assays. We gratefully thank Monika Zimmermann and Celestine Dutta (Institute of Neurogenomics, Helmholtz Center Munich) for their generous contribution with immunoblotting analyses. We further thank Frauke Hinrichs (Institute of Neurogenetics, University of Lübeck) for technical support. Open Access funding enabled and organized by Projekt DEAL.
Keywords
- EIF4A2
- dystonia
- loss-of-function variants
- translational dysfunction
- tremor
ASJC Scopus subject areas
- Neurology
- Clinical Neurology