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EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

Annals of Neurology, ISSN: 1531-8249, Vol: 89, Issue: 3, Page: 485-497
2021
  • 39
    Citations
  • 0
    Usage
  • 61
    Captures
  • 0
    Mentions
  • 40
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    39
  • Captures
    61
  • Social Media
    40
    • Shares, Likes & Comments
      40
      • Facebook
        40

Article Description

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.

Bibliographic Details

Kuipers, Demy J S; Mandemakers, Wim; Lu, Chin-Song; Olgiati, Simone; Breedveld, Guido J; Fevga, Christina; Tadic, Vera; Carecchio, Miryam; Osterman, Bradley; Sagi-Dain, Lena; Wu-Chou, Yah-Huei; Chen, Chiung C; Chang, Hsiu-Chen; Wu, Shey-Lin; Yeh, Tu-Hsueh; Weng, Yi-Hsin; Elia, Antonio E; Panteghini, Celeste; Marotta, Nicolas; Pauly, Martje G; Kühn, Andrea A; Volkmann, Jens; Lace, Baiba; Meijer, Inge A; Kandaswamy, Krishna; Quadri, Marialuisa; Garavaglia, Barbara; Lohmann, Katja; Bauer, Peter; Mencacci, Niccolò E; Lubbe, Steven J; Klein, Christine; Bertoli-Avella, Aida M; Bonifati, Vincenzo

Wiley

Neuroscience; Medicine

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