title: CACNA1A variants may modify the epileptic phenotype of Dravet syndrome.
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.
authors.affiliation: Department of Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Shikatacho 2-chome 5-1, Kita-ku, Okayama 700-8558, Japan. iori@md.okayama-u.ac.jp
authors.forename: Iori
authors.initials: I
authors.lastname: Ohmori
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ouchida
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Jitsumori
authors.forename: Akiko
authors.initials: A
authors.lastname: Mori
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Michiue
authors.forename: Teiichi
authors.initials: T
authors.lastname: Nishiki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ohtsuka
authors.forename: Hideki
authors.initials: H
authors.lastname: Matsui
mesh_terms: D000328:Adult; D001483:Base Sequence; D015220:Calcium Channels / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000503:physiopathology*; D005838:Genotype; D006801:Humans; D008969:Molecular Sequence Data; D018408:Patch-Clamp Techniques; D010641:Phenotype; D020864:Calcium Channels, N-Type
chemical_list: D015220:Calcium Channels; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type