EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia PMID: 33236446

ADC Targets in Oncology

2026-04-10

EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

Ann Neurol. 2021 Mar;89(3):485-497. doi: 10.1002/ana.25973.

Demy J S Kuipers ¹ , Wim Mandemakers ¹ , Chin-Song Lu ² ³ , Simone Olgiati ¹ , Guido J Breedveld ¹ , Christina Fevga ¹ , Vera Tadic ⁴ , Miryam Carecchio ⁵ ⁶ , Bradley Osterman ⁷ , Lena Sagi-Dain ⁸ , Yah-Huei Wu-Chou ⁹ , Chiung C Chen ³ ¹⁰ , Hsiu-Chen Chang ² ³ , Shey-Lin Wu ¹¹ , Tu-Hsueh Yeh ¹² ¹³ , Yi-Hsin Weng ³ ¹⁰ , Antonio E Elia ¹⁴ , Celeste Panteghini ⁵ , Nicolas Marotta ¹⁵ , Martje G Pauly ⁴ , Andrea A Kühn ¹⁶ , Jens Volkmann ¹⁷ , Baiba Lace ¹⁸ , Inge A Meijer ¹⁹ , Krishna Kandaswamy ²⁰ , Marialuisa Quadri ¹ ²¹ , Barbara Garavaglia ⁵ , Katja Lohmann ⁴ , Peter Bauer ²⁰ , Niccolò E Mencacci ¹⁵ , Steven J Lubbe ¹⁵ , Christine Klein ⁴ , Aida M Bertoli-Avella ²⁰ , Vincenzo Bonifati ¹

Affiliations

1. Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
2. Professor Lu Neurological Clinic, Taoyuan, Taiwan.
3. Section of Movement Disorders, Department of Neurology and Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
4. Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
5. Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy.
6. Department of Neuroscience, University of Padua, Padua, Italy.
7. Division of Child Neurology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
8. Genetics Institute, Carmel Medical Center, Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
9. Department of Medical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
10. Department of Medicine, Chang Gung University, Taoyuan, Taiwan.
11. Department Neurology, Changhua Christian Hospital, Chunghua, Taiwan.
12. Department of Neurology, Taipei Medical University Hospital, Taipei, Taiwan.
13. School of Medicine, Taipei Medical University, Taipei, Taiwan.
14. Department of Clinical Neurosciences, Parkinson and Movement Disorders Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
15. Ken and Ruth Davee Department of Neurology and Simpson Querry Center for Neurogenetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
16. 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.
17. Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
18. Centre Hospitalier Universitaire de Québec, Quebec City, Quebec, Canada.
19. Department of Neurosciences and Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, Quebec, Canada.
20. Centogene AG, Rostock, Germany.
21. Janssen Vaccines and Prevention, Leiden, the Netherlands.

Abstract

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.