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

See more in PubMed

Balint B, Mencacci NE, Valente EM, et al. Dystonia. Nat Rev Dis Primers 2018;4(1):25.

Keller Sarmiento IJ, Mencacci NE. Genetic Dystonias: update on classification and new genetic discoveries. Curr Neurol Neurosci Rep 2021;21(3):8.

Gonzalez-Latapi P, Marotta N, Mencacci NE. Emerging and converging molecular mechanisms in dystonia. J Neural Transm (Vienna) 2021;128(4):483-498.

Advani VM, Ivanov P. Translational control under stress: reshaping the Translatome. Bioessays 2019;41(5):e1900009.

Sossin WS, Costa-Mattioli M. Translational Control in the Brain in Health and Disease. Cold Spring Harb Perspect Biol 2019;11(8):a032912.

Wiebe S, Nagpal A, Sonenberg N. Dysregulated translational control in brain disorders: from genes to behavior. Curr Opin Genet Dev 2020;65:34-41.

Sleiman S, Marshall AE, Dong X, et al. Compound heterozygous variants in SHQ1 are associated with a spectrum of neurological features, including early-onset dystonia. Hum Mol Genet 2022;31(4):614-624.

Rittiner JE, Caffall ZF, Hernandez-Martinez R, et al. Functional genomic analyses of Mendelian and sporadic disease identify impaired eIF2alpha signaling as a generalizable mechanism for dystonia. Neuron 2016;92(6):1238-1251.

Cagnetta R, Wong HH, Frese CK, Mallucci GR, Krijgsveld J, Holt CE. Noncanonical modulation of the eIF2 pathway controls an increase in local translation during neural wiring. Mol Cell 2019;73(3):474-489e475.

Bellato HM, Hajj GN. Translational control by eIF2alpha in neurons: beyond the stress response. Cytoskeleton (Hoboken) 2016;73(10):551-565.

Hershey JW, Sonenberg N, Mathews MB. Principles of translational control: an overview. Cold Spring Harb Perspect Biol 2012;4(12):a011528.

Beauvais G, Watson JL, Aguirre JA, Tecedor L, Ehrlich ME, Gonzalez-Alegre P. Efficient RNA interference-based knockdown of mutant torsinA reveals reversibility of PERK-eIF2alpha pathway dysregulation in DYT1 transgenic rats in vivo. Brain Res 2019;1706:24-31.

Zakirova Z, Fanutza T, Bonet J, et al. Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions. PLoS Genet 2018;14(1):e1007169.

Camargos S, Scholz S, Simon-Sanchez J, et al. DYT16, a novel young-onset dystonia-parkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA. Lancet Neurol 2008;7(3):207-215.

Kuipers DJS, Mandemakers W, Lu CS, et al. EIF2AK2 missense variants associated with early onset generalized dystonia. Ann Neurol 2020;89(3):485-497.

Mao D, Reuter CM, Ruzhnikov MRZ, et al. De novo EIF2AK1 and EIF2AK2 variants are associated with developmental delay, leukoencephalopathy, and neurologic decompensation. Am J Hum Genet 2020;106(4):570-583.

Musacchio T, Zech M, Reich MM, Winkelmann J, Volkmann J. A recurrent EIF2AK2 missense variant causes autosomal-dominant isolated dystonia. Ann Neurol 2021;89(6):1257-1258.

Paul MS, Duncan AR, Genetti CA, et al. Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy. Am J Hum Genet 2023;110(1):120-145.

Zech M, Jech R, Boesch S, et al. Monogenic variants in dystonia: an exome-wide sequencing study. Lancet Neurol 2020;19(11):908-918.

Dzinovic I, Boesch S, Skorvanek M, et al. Genetic overlap between dystonia and other neurologic disorders: a study of 1,100 exomes. Parkinsonism Relat Disord 2022;102:1-6.

Wilczynska A, Gillen SL, Schmidt T, et al. eIF4A2 drives repression of translation at initiation by Ccr4-not through purine-rich motifs in the 5'UTR. Genome Biol 2019;20(1):262.

Zech M, Kumar KR, Reining S, et al. Biallelic AOPEP loss-of-function variants cause progressive dystonia with prominent limb involvement. Mov Disord 2022;37(1):137-147.

Zech M, Kopajtich R, Steinbrucker K, et al. Variants in mitochondrial ATP synthase cause variable neurologic phenotypes. Ann Neurol 2022;91(2):225-237.

Steel D, Zech M, Zhao C, et al. Loss-of-function variants in HOPS complex genes VPS16 and VPS41 cause early onset dystonia associated with lysosomal abnormalities. Ann Neurol 2020;88(5):867-877.

Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020;581(7809):434-443.

Kumar KR, Davis RL, Tchan MC, et al. Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes. Parkinsonism Relat Disord 2019;69:111-118.

Meijer HA, Schmidt T, Gillen SL, et al. DEAD-box helicase eIF4A2 inhibits CNOT7 deadenylation activity. Nucleic Acids Res 2019;47(15):8224-8238.

Jia X, Zhang S, Tan S, et al. De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders. Sci Adv 2022;8(33):eabo7112.

Li K, Ling Z, Luo T, et al. Cross-disorder analysis of De novo variants increases the power of Prioritising candidate genes. Life (Basel) 2021;11(3):233.

Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17(5):405-424.

Charlesworth G, Plagnol V, Holmstrom KM, et al. Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis. Am J Hum Genet 2012;91(6):1041-1050.

Mencacci NE, Rubio-Agusti I, Zdebik A, et al. A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia. Am J Hum Genet 2015;96(6):938-947.

Ozelius LJ, Hewett JW, Page CE, et al. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat Genet 1997;17(1):40-48.

Meyer E, Carss KJ, Rankin J, et al. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat Genet 2017;49(2):223-237.

Burgunder JM. Mechanisms underlying phenotypic variation in neurogenetic disorders. Nat Rev Neurol 2023;19(6):363-370.

Harel T, Yesil G, Bayram Y, et al. Monoallelic and Biallelic variants in EMC1 identified in individuals with global developmental delay, Hypotonia, scoliosis, and cerebellar atrophy. Am J Hum Genet 2016;98(3):562-570.

Steel D, Vezyroglou A, Barwick K, et al. Both heterozygous and homozygous loss-of-function JPH3 variants are associated with a paroxysmal movement disorder. Mov Disord 2023;38(1):155-157.

Kingdom R, Tuke M, Wood A, et al. Rare genetic variants in genes and loci linked to dominant monogenic developmental disorders cause milder related phenotypes in the general population. Am J Hum Genet 2022;109(7):1308-1316.

Dzinovic I, Winkelmann J, Zech M. Genetic intersection between dystonia and neurodevelopmental disorders: insights from genomic sequencing. Parkinsonism Relat Disord 2022;102:131-140.

von Scheibler E, van Eeghen AM, de Koning TJ, et al. Parkinsonism in genetic neurodevelopmental disorders: a systematic review. Mov Disord Clin Pract 2023;10(1):17-31.

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