EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia.

Autor: Kuipers DJS; Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands., Mandemakers W; Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands., Lu CS; Professor Lu Neurological Clinic, Taoyuan, Taiwan.; Section of Movement Disorders, Department of Neurology and Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan., Olgiati S; Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands., Breedveld GJ; Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands., Fevga C; Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands., Tadic V; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany., Carecchio M; Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy.; Department of Neuroscience, University of Padua, Padua, Italy., Osterman B; Division of Child Neurology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada., Sagi-Dain L; Genetics Institute, Carmel Medical Center, Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel., Wu-Chou YH; Department of Medical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan., Chen CC; Section of Movement Disorders, Department of Neurology and Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.; Department of Medicine, Chang Gung University, Taoyuan, Taiwan., Chang HC; Professor Lu Neurological Clinic, Taoyuan, Taiwan.; Section of Movement Disorders, Department of Neurology and Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan., Wu SL; Department Neurology, Changhua Christian Hospital, Chunghua, Taiwan., Yeh TH; Department of Neurology, Taipei Medical University Hospital, Taipei, Taiwan.; School of Medicine, Taipei Medical University, Taipei, Taiwan., Weng YH; Section of Movement Disorders, Department of Neurology and Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.; Department of Medicine, Chang Gung University, Taoyuan, Taiwan., Elia AE; Department of Clinical Neurosciences, Parkinson and Movement Disorders Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy., Panteghini C; Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy., Marotta N; Ken and Ruth Davee Department of Neurology and Simpson Querry Center for Neurogenetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA., Pauly MG; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany., Kühn AA; Department of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität of Berlin and Humboldt, Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Volkmann J; Department of Neurology, University Hospital Würzburg, Würzburg, Germany., Lace B; Centre Hospitalier Universitaire de Québec, Quebec City, Quebec, Canada., Meijer IA; Department of Neurosciences and Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, Quebec, Canada., Kandaswamy K; Centogene AG, Rostock, Germany., Quadri M; Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.; Janssen Vaccines and Prevention, Leiden, the Netherlands., Garavaglia B; Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy., Lohmann K; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany., Bauer P; Centogene AG, Rostock, Germany., Mencacci NE; Ken and Ruth Davee Department of Neurology and Simpson Querry Center for Neurogenetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA., Lubbe SJ; Ken and Ruth Davee Department of Neurology and Simpson Querry Center for Neurogenetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA., Klein C; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany., Bertoli-Avella AM; Centogene AG, Rostock, Germany., Bonifati V; Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Jazyk: angličtina
Zdroj: Annals of neurology [Ann Neurol] 2021 Mar; Vol. 89 (3), pp. 485-497. Date of Electronic Publication: 2020 Dec 15.
DOI: 10.1002/ana.25973
Abstrakt: Objective: The study was undertaken to identify a monogenic cause of early onset, generalized dystonia.
Methods: Methods consisted of genome-wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain magnetic resonance imaging, and protein expression studies in skin fibroblasts from patients.
Results: We identified a heterozygous variant, c.388G>A, p.Gly130Arg, in the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) gene, segregating with early onset isolated generalized dystonia in 5 patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded 2 unrelated Caucasian patients with an identical heterozygous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G>C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A>C, p.Asn32Thr. These 3 missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In 3 patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (protein kinase R [PKR]) that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR-mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA (protein interferon-inducible double-stranded RNA-dependent protein kinase activator A), the product of another gene causing monogenic dystonia.
Interpretation: We identified EIF2AK2 variants implicated in early onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2α pathway in the pathogenesis of dystonia. ANN NEUROL 2021;89:485-497.
(© 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
Databáze: MEDLINE
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