Dystonia 16 (DYT16) mutations in PACT cause dysregulated PKR activation and eIF2α signaling leading to a compromised stress response

Burnett, Samuel B.; Vaughn, Lauren S.; Sharma, Nutan; Kulkarni, Ronit; Patel, Rekha C.

doi:10.1016/j.nbd.2020.105135

Cited by 22 publications

(27 citation statements)

References 76 publications

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“…Evidence for a disturbed integrated stress response (ISR) has been previously reported in other monogenic causes of dystonia, including DYT‐PRKRA, DYT‐TOR1A, DYT‐THAP1, and DYT‐SGCE. Several studies have shown that variants in the PRKRA gene enhanced the susceptibility to endoplasmic reticulum stress leading to heightened EIF2AK2 activation, dysregulation of ISR, and increased apoptosis 32,34,35 . ISR dysregulation has been reported to play a central role in DYT‐TOR1A 10,11,36 .…”

Section: Discussionmentioning

confidence: 99%

EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

Kuipers

Mandemakers

et al. 2020

Annals of Neurology

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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

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Section: Discussionmentioning

confidence: 99%

EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

Kuipers

Mandemakers

et al. 2020

Annals of Neurology

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“…The p. (Pro222Leu) variant produces an altered kinetic response to ER-stress. It is thought to foster stronger homo-dimer interactions with itself and with the RNA-activated protein kinase, PKR, leading to an aberrant stress response with a concomitant increase in apoptosis ( Vaughn et al, 2015 ; Burnett et al, 2020 ). While the age-of-onset for P2 (3 years) is slightly younger than previous reports (average 8 years (range: 4–14 years) ( Lange et al, 2021 ), the phenotype is otherwise typical of Dystonia 16, with predominant dysarthria.…”

Section: Discussionmentioning

confidence: 99%

Uniparental disomy screen of Irish rare disorder cohort unmasks homozygous variants of clinical significance in the TMCO1 and PRKRA genes

Molloy¹,

Jones²,

Linhares³

et al. 2022

Front. Genet.

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A uniparental disomy (UPD) screen using whole genome sequencing (WGS) data from 164 trios with rare disorders in the Irish population was performed to identify large runs of homozygosity of uniparental origin that may harbour deleterious recessive variants. Three instances of whole chromosome uniparental isodisomy (UPiD) were identified: one case of maternal isodisomy of chromosome 1 and two cases of paternal isodisomy of chromosome 2. We identified deleterious homozygous variants on isodisomic chromosomes in two probands: a novel p (Glu59ValfsTer20) variant in TMCO1, and a p (Pro222Leu) variant in PRKRA, respectively. The overall prevalence of whole chromosome UPiD in our cohort was 1 in 55 births, compared to 1 in ∼7,500 births in the general population, suggesting a higher frequency of UPiD in rare disease cohorts. As a distinct mechanism underlying homozygosity compared to biallelic inheritance, the identification of UPiD has important implications for family planning and cascade testing. Our study demonstrates that UPD screening may improve diagnostic yields by prioritising UPiD chromosomes during WGS analysis.

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“…Previously, our lab reported that four recessively inherited and two dominantly inherited PACT substitution mutations increase cell susceptibility to ER stress by causing elevated levels of PKR activation and eIF2α phosphorylation that also persist for a longer duration in DYT- PRKRA patient-derived lymphoblasts ( Vaughn et al, 2015 ; Burnett et al, 2020 ). Furthermore, a truncated PACT protein resulting from a dominantly inherited frameshift mutation, increased PACT-mediated PKR activation, and an enhanced sensitivity to ER stress also via causing PKR activation and eIF2α phosphorylation ( Burnett et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Luteolin protects DYT-PRKRA cells from apoptosis by suppressing PKR activation

Frederick

Patel

2023

Front. Pharmacol.

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DYT-PRKRA is a movement disorder caused by mutations in the PRKRA gene, which encodes for PACT, the protein activator of interferon-induced, double-stranded RNA (dsRNA)-activated protein kinase PKR. PACT brings about PKR’s catalytic activation by a direct binding in response to stress signals and activated PKR phosphorylates the translation initiation factor eIF2α. Phosphorylation of eIF2α is the central regulatory event that is part of the integrated stress response (ISR), an evolutionarily conserved intracellular signaling network essential for adapting to environmental stresses to maintain healthy cells. A dysregulation of either the level or the duration of eIF2α phosphorylation in response to stress signals causes the normally pro-survival ISR to become pro-apoptotic. Our research has established that the PRKRA mutations reported to cause DYT-PRKRA lead to enhanced PACT-PKR interactions causing a dysregulation of ISR and an increased sensitivity to apoptosis. We have previously identified luteolin, a plant flavonoid, as an inhibitor of the PACT-PKR interaction using high-throughput screening of chemical libraries. Our results presented in this study indicate that luteolin is markedly effective in disrupting the pathological PACT-PKR interactions to protect DYT-PRKRA cells against apoptosis, thus suggesting a therapeutic option for using luteolin to treat DYT-PRKRA and possibly other diseases resulting from enhanced PACT-PKR interactions.

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Dystonia 16 (DYT16) mutations in PACT cause dysregulated PKR activation and eIF2α signaling leading to a compromised stress response

Cited by 22 publications

References 76 publications

EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

Uniparental disomy screen of Irish rare disorder cohort unmasks homozygous variants of clinical significance in the TMCO1 and PRKRA genes

Luteolin protects DYT-PRKRA cells from apoptosis by suppressing PKR activation

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