TY - JOUR
T1 - EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia
AU - Kuipers, Demy J.S.
AU - Mandemakers, Wim
AU - Lu, Chin Song
AU - Olgiati, Simone
AU - Breedveld, Guido J.
AU - Fevga, Christina
AU - Tadic, Vera
AU - Carecchio, Miryam
AU - Osterman, Bradley
AU - Sagi-Dain, Lena
AU - Wu-Chou, Yah Huei
AU - Chen, Chiung C.
AU - Chang, Hsiu Chen
AU - Wu, Shey Lin
AU - Yeh, Tu Hsueh
AU - Weng, Yi Hsin
AU - Elia, Antonio E.
AU - Panteghini, Celeste
AU - Marotta, Nicolas
AU - Pauly, Martje G.
AU - Kühn, Andrea A.
AU - Volkmann, Jens
AU - Lace, Baiba
AU - Meijer, Inge A.
AU - Kandaswamy, Krishna
AU - Quadri, Marialuisa
AU - Garavaglia, Barbara
AU - Lohmann, Katja
AU - Bauer, Peter
AU - Mencacci, Niccolò E.
AU - Lubbe, Steven J.
AU - Klein, Christine
AU - Bertoli-Avella, Aida M.
AU - Bonifati, Vincenzo
N1 - Publisher Copyright:
© 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85097551907
U2 - 10.1002/ana.25973
DO - 10.1002/ana.25973
M3 - 文章
C2 - 33236446
AN - SCOPUS:85097551907
SN - 0364-5134
VL - 89
SP - 485
EP - 497
JO - Annals of Neurology
JF - Annals of Neurology
IS - 3
ER -