Abstract
Dravet syndrome is an intractable epileptic syndrome beginning in the first year of life. De novo mutations of SCN1A, which encode the Nav1.1 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 Cav2.1 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 Cav2.1 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.
| Original language | English |
|---|---|
| Pages (from-to) | 209-217 |
| Number of pages | 9 |
| Journal | Neurobiology of Disease |
| Volume | 50 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Feb 2013 |
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Keywords
- CACNA1A
- Electrophysiology
- Epilepsy
- Molecular genetics
- SCN1A
ASJC Scopus subject areas
- Neurology
Cite this
CACNA1A variants may modify the epileptic phenotype of Dravet syndrome. / Ohmori, Iori; Oouchida, Mamoru; Kobayashi, Katsuhiro; Jitsumori, Yoshimi; Mori, Akiko; Michiue, Hiroyuki; Nishiki, Tei-ichi; Ohtsuka, Yoko; Matsui, Hideki.
In: Neurobiology of Disease, Vol. 50, No. 1, 02.2013, p. 209-217.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - CACNA1A variants may modify the epileptic phenotype of Dravet syndrome
AU - Ohmori, Iori
AU - Oouchida, Mamoru
AU - Kobayashi, Katsuhiro
AU - Jitsumori, Yoshimi
AU - Mori, Akiko
AU - Michiue, Hiroyuki
AU - Nishiki, Tei-ichi
AU - Ohtsuka, Yoko
AU - Matsui, Hideki
PY - 2013/2
Y1 - 2013/2
N2 - Dravet syndrome is an intractable epileptic syndrome beginning in the first year of life. De novo mutations of SCN1A, which encode the Nav1.1 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 Cav2.1 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 Cav2.1 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.
AB - Dravet syndrome is an intractable epileptic syndrome beginning in the first year of life. De novo mutations of SCN1A, which encode the Nav1.1 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 Cav2.1 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 Cav2.1 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.
KW - CACNA1A
KW - Electrophysiology
KW - Epilepsy
KW - Molecular genetics
KW - SCN1A
UR - http://www.scopus.com/inward/record.url?scp=84870192590&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84870192590&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2012.10.016
DO - 10.1016/j.nbd.2012.10.016
M3 - Article
C2 - 23103419
AN - SCOPUS:84870192590
VL - 50
SP - 209
EP - 217
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
IS - 1
ER -