Dataset Information

DYT30 due to VPS16 Mutation: An Etiology of Childhood-Onset Generalized Dystonia.

ABSTRACT:

SUBMITTER: Shashi S

PROVIDER: S-EPMC10394456 | biostudies-literature | 2023 May-Jun

REPOSITORIES: biostudies-literature

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DYT30 due to <i>VPS16</i> Mutation: An Etiology of Childhood-Onset Generalized Dystonia.

Shashi Sridhar S Nashi Saraswati S Arunachal Gautham G Venkatachalam N N Padmanabha Hansashree H Mailankody Pooja P Menon Deepak D Arshad Faheem F Alladi Suvarna S Mathuranath Pavagada P Mahale Rohan R RR

Annals of Indian Academy of Neurology 20230420 3

PMID: 37538408

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Project description: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.

Dataset Information

DYT30 due to VPS16 Mutation: An Etiology of Childhood-Onset Generalized Dystonia.

Publications

DYT30 due to <i>VPS16</i> Mutation: An Etiology of Childhood-Onset Generalized Dystonia.

Similar Datasets

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