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ID 56950
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Ohmori, Iori Department of Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kakenhi
Ouchida, Mamoru Department of Molecular Genetics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kakenhi
Kobayashi, Katsuhiro
Jitsumori, Yoshimi
Mori, Akiko Department of Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Michiue, Hiroyuki Department of Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kakenhi
Nishiki, Teiichi Department of Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kakenhi
Ohtsuka, Yoko
Matsui, Hideki Department of Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kakenhi
Abstract
Dravet syndrome is an intractable epileptic syndrome beginning in the first year of life. De novo mutations of SCN1A, which encode the Na(v)1.1 neuronal voltage-gated sodium channel, are considered the major cause of Dravet syndrome. In this study, we investigated genetic modifiers of this syndrome. We performed a mutational analysis of all coding exons of CACNA1A in 48 subjects with Dravet syndrome. To assess the effects of CACNA1A variants on the epileptic phenotypes of Dravet syndrome, we compared clinical features in two genotype groups: 1) subjects harboring SCN1A mutations but no CACNA1A variants (n=20) and 2) subjects with SCN1A mutations plus CACNA1A variants (n=20). CACNA1A variants detected in patients were studied using heterologous expression of recombinant human Ca(v)2.1 in HEK 293 cells and whole-cell patch-clamp recording. Nine CACNA1A variants, including six novel ones, were detected in 21 of the 48 subjects (43.8%). Based on the incidence of variants in healthy controls, most of the variants seemed to be common polymorphisms. However, the subjects harboring SCN1A mutations and CACNA1A variants had absence seizures more frequently than the patients with only SCN1A mutations (8/20 vs. 0/20, p=0.002). Moreover, the former group of subjects exhibited earlier onset of seizures and more frequent prolonged seizures before one year of age, compared to the latter group of subjects. The electrophysiological properties of four of the five novel Ca(v)2.1 variants exhibited biophysical changes consistent with gain-of-function. We conclude that CACNA1A variants in some persons with Dravet syndrome may modify the epileptic phenotypes.
Note
CACNA1A variants contribute to severity of seizures in Dravet syndrome
Published Date
2013-02
Publication Title
Neurobiology of disease
Volume
volume50
Publisher
Academic Press
Start Page
209
End Page
217
ISSN
09699961
NCID
AA11645502
Content Type
Journal Article
language
英語
OAI-PMH Set
岡山大学
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isVersionOf https://doi.org/10.1016/j.nbd.2012.10.016
Citation
Iori Ohmori, Mamoru Ouchida, Katsuhiro Kobayashi, Yoshimi Jitsumori, Akiko Mori, Hiroyuki Michiue, Teiichi Nishiki, Yoko Ohtsuka, Hideki Matsui, CACNA1A variants may modify the epileptic phenotype of Dravet syndrome, Neurobiology of Disease, Volume 50, 2013, Pages 209-217, ISSN 0969-9961, https://doi.org/10.1016/j.nbd.2012.10.016.
Funder Name
Ministry of Education, Culture, Sports, Science and Technology
助成番号
21390312