ArticleAnnals of neurology2021
EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia.
Article in Annals of neurology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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38 citing papers in PubMed, 64 citations in OpenAlex.
- Secondary Pharmacology Targets for Pediatric Developmental Safety Assessment of New Drugs: Clinical Pharmacology Considerations.Clinical pharmacology and therapeutics · 2026Review
- Single-cell transcriptomics and mouse model phenotyping for biomarker screen of peripheral blood in Huntington's disease.Scientific reports · 2026Article
- EIF2AK2-related hypomyelinating leukoencephalopathy presenting with congenital bilateral vocal cord paralysis and a spinal cord lesion.Neurogenetics · 2026Article
- Generalized dystonia unraveled: Molecular mechanisms, diagnostic strategies, and treatment paradigms.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Review
- Article
- Neurobiology of Dystonia: Review of Genetics, Animal Models, and Neuroimaging.Brain sciences · 2025Review
- Human pegivirus alters brain and blood immune and transcriptomic profiles of patients with Parkinson's disease.JCI insight · 2025Article
- Pediatric Genetic Dystonias: Current Diagnostic Approaches and Treatment Options.Life (Basel, Switzerland) · 2025Review
- The comprehensive transcriptomic atlas of porcine immune tissues and the peripheral blood mononuclear cell (PBMC) immune dynamics reveal core immune genes.Journal of animal science and biotechnology · 2025Article
- A Chinese Child With Dystonia Linked to the EIF2AK2 Missense Variant: A Case Report.Journal of movement disorders · 2025Article
- Emerging Molecular-Genetic Families in Dystonia: Endosome-Autophagosome-Lysosome and Integrated Stress Response Pathways.Movement disorders : official journal of the Movement Disorder Society · 2025Review
- Sterile activation of RNA-sensing pathways in autoimmunity.Journal of molecular cell biology · 2024Review
- Mutation in Prkra results in cerebellar abnormality and reduced eIF2α phosphorylation in a model of DYT-PRKRA.Disease models & mechanisms · 2024Article
- Heterozygous de novo dominant negative mutation of REXO2 results in interferonopathy.Nature communications · 2024Article
- The integrated stress response in brain diseases: A double-edged sword for proteostasis and synapses.Current opinion in neurobiology · 2024Review
- Blood-Based Proteomics for Adult-Onset Focal Dystonias.Annals of neurology · 2024Article
- Whole-exome sequencing in a cohort of Chinese patients with isolated cervical dystonia.Heliyon · 2024Article
- A frameshift mutation in the murinebioRxiv : the preprint server for biology · 2024Article
- eIF2α phosphorylation evokes dystonia-like movements with D2-receptor and cholinergic origin and abnormal neuronal connectivity.bioRxiv : the preprint server for biology · 2024Article
- The integrated stress response pathway and neuromodulator signaling in the brain: lessons learned from dystonia.The Journal of clinical investigation · 2024Review
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Authors and funding
34 authors at 16 institutions in 7 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveThe study was undertaken to identify a monogenic cause of early onset, generalized dystonia.
methodsMethods 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.
resultsWe 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.
interpretationWe 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.
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