EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia
| Autor: | Lena Sagi-Dain, Martje G. Pauly, Chiung C. Chen, Niccolo E. Mencacci, Shey Lin Wu, Inge A. Meijer, Aida M. Bertoli-Avella, Krishna Kumar Kandaswamy, Steven J. Lubbe, Celeste Panteghini, Wim Mandemakers, Christine Klein, Nicolas Marotta, Katja Lohmann, Peter Bauer, Andrea A. Kühn, Baiba Lace, Vincenzo Bonifati, Tu Hsueh Yeh, Chin Song Lu, Miryam Carecchio, Antonio E. Elia, Christina Fevga, Yah Huei Wu-Chou, Yi Hsin Weng, Vera Tadic, Bradley Osterman, Marialuisa Quadri, Barbara Garavaglia, Simone Olgiati, Guido J. Breedveld, Jens Volkmann, Hsiu Chen Chang, Demy J.S. Kuipers |
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| Přispěvatelé: | Clinical Genetics |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Adult Male Adolescent Mutation Missense Biology White People 03 medical and health sciences symbols.namesake Young Adult eIF-2 Kinase 0302 clinical medicine Asian People Genetic linkage Exome Sequencing medicine Missense mutation Humans Age of Onset Protein kinase A Child Exome Research Articles Dystonia Sanger sequencing Genetics Kinase Brain Infant Fibroblasts Middle Aged medicine.disease Protein kinase R Magnetic Resonance Imaging Pedigree 030104 developmental biology Neurology Dystonic Disorders Child Preschool symbols Female Neurology (clinical) 030217 neurology & neurosurgery Genome-Wide Association Study Research Article |
| Zdroj: | Annals of Neurology Annals of Neurology, 89(3), 485-497. John Wiley & Sons Inc. |
| ISSN: | 0364-5134 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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