てんかんおよび熱性けいれんの遺伝子解析

2001 Fiscal Year Annual Research Report

• Project/Area Number: 12307019
• Research Institution: Hirosaki University
• Principal Investigator: 兼子 直 弘前大学, 医学部, 教授 (40106852)
• Co-Investigator(Kenkyū-buntansha): 満留 昭久 福岡大学, 医学部, 教授 (30038749) ; 佐野 輝 愛媛大学, 医学部, 助教授 (30178800) ; 辻 省次 新潟大学, 脳研究所, 教授 (70150612) ; 伊藤 正利 滋賀県立小児保健医療センター, 副部長(研究職) (90135567) ; 山川 和弘 理化学研究所, 脳科学総合センター, チームリーダー (30241235)
• Keywords: GEFS+ / SCN1A / SCN2A / GABA receptor / Chorein / Juvenile myoclonic epilepsy / BFNC / BFNC

Research Abstract

1.熱性けいれんプラス(generalized epilepsy febrile seizure plus : GEFS+)関連
世界に先駆け、GEFS+の責任遺伝子の一つとしてNa+イオンチャネルSCN2Aを同定し、同時にSCN1Aの変異も複数発見し報告した。一方、変異遺伝子と臨床類型の研究から、GEFS+症例には部分発作を伴うことを見いだし、GEFS+はAutosomal dominant epilepsy with febrile seizures plusと命名すべきことを指摘した。
2.てんかん発作を伴うchorea acanthocytosisの責任遺伝子である新奇蛋白choreinを同定した。
3.Severe myoclonic epilepsy in infancy(SMEI)の責任遺伝子として、Na+イオンチャネルSCN1Aにおける複数の変異を同定し、SMEIにはGABA-A受容体のγ2サブユニットの変異も関連することを発見し、投稿中である。
4.Juvenile myoclonic epilepsyの強力な候補遺伝子を発見し、投稿中である。
5.良性家族性新生児けいれんの(BFNC)責任遺伝子であるKCNQ2,3が発作を起こすが、その発作発現と消失に関わる分子病態を明らかにした。
6.以上のような研究の進展に伴い、2002年度は欠神発作などの頻度の高いてんかん類型の遺伝子座位を決定する目的で、ゲノムワイドスキャンを行う予定である。

Research Products

• [Publications] M Okada, et al.: "Impaired M-current and neuronal excitability"Epilepsia. (In press). (2002)
• [Publications] M Ito, et al.: "Autosomal dominant epilepsy with febrile seizures plus with missense mutations of the (Na^+)-channel α1 subunit gene, SCN1A"Epilepsy Research. 48(In press). (2002)
• [Publications] T Takahashi, et al.: "Japanese cases of familial hemiplegic migraine with cerebellar ataxia carrying a T666M mutation in the CACNA1A gene"Journal of Neurology Neurosurgery and Psychitry. (In press). (2002)
• [Publications] N Matsushima, et al.: "Mutation (Ser284Leu) of neuronal nicotinic acetylcholine receptor α 4 subunit associated with frontal lobe epilepsy causes faster desensitization of the rat receptor expressed in oocytes"Epilepsy Research. 48. 15-23 (2002)
• [Publications] M Ito, et al.: "Low-dose ACTH therapy for West syndrome : Initial effects and long-term outcome"Neurology. 58(1-2). 110-114 (2002)
• [Publications] M Ito: "Extremely low-dose ACTH therapy for West syndrome in Japan"Brain & Development. 23. 635-641 (2001)
• [Publications] T Murakami, et al.: "Determination of effects of antiepileptio drugs on SNARs-mediated hippocampal monoamine release using in vivo microdialysis"British Journal of Pharmacology. 134. 507-520 (2001)
• [Publications] I Yoshimura, et al.: "Long-term observations of two siblings with Lafora disease treated with zonisamide"Epilepsy Research. 46. 283-287 (2001)
• [Publications] S Ueno, et al.: "The gene encoding a newly discovered protein, chorein, is mutated in chorea-acanthocytosis"Nature Genetics. 28(7). 121-122 (2001)
• [Publications] Y Kawata, et al.: "Pharmacological discrimination between effects of carbamazepine on hippocampal basal, Ca^<2+>-and K^+ evoked serotonin releases"British Journal of Pharmacology. 133. 557-567 (2001)
• [Publications] K Wada, et al.: "Sociomedical aspects of epileptic patients : Their employment and marital status"Psychiatry and Clinical Neurosciences. 55(2). 141-146 (2001)
• [Publications] M Okada, et al.: "Adenosin receptor subtypes modulate two major functional pathways for hippocampal serotonin release"Journal of Neuroscience. 21(2). 628-640 (2001)
• [Publications] Y Sugimoto, et al.: "T-STAR gene : fine mapping in the candidate region for childhood absence epilepsy on 8q24 and mutational analysis in patients"Epilepsy Research. 46. 139-144 (2001)
• [Publications] T Suzuki, et al.: "A novel gene in the chromosomal region for juvenile myoclonic epilepsy on 6q12 encodes a brain-specific lysosomal membrane protein"Biochemical and Biophysical Research Communications. 288. 626-636 (2001)
• [Publications] T Sugawara, et al.: "Na_v1.1 mutations cause febrile seizures associated with afebrile partial seizures"Neurology. 57. 703-705 (2001)
• [Publications] T Sugawara, et al.: "A missense mutation of the Na^+ channel α_<II> subunit gene Na_v1.2 in a patients with febrile and afebrile seizures causes channel dysfunction"P NATL ACAD SCI USA. 98(11). 6384-6389 (2001)
• [Publications] S Ganesh, et al.: "Regional and development expression of Epm2a gene and its evolutionary conservation"Biochemical and Biophysical Research Communications. 283. 1046-1053 (2001)
• [Publications] S Ganesh, et al.: "Mutation screening for Japanese Lafore's disease patients : Identification of novel sequence variants in the coding and upstream regulatory regions of EPM2A gene"Molecular and Cellular Probes. 15. 281-289 (2001)
• [Publications] H Oguni, et al.: "Study on early-onset benign occipital seizure susceptibility syndrome"Pediatric Neurology. 25(4). 312-318 (2001)
• [Publications] E Tachikawa, et al.: "Acquired epileptiform opercular syndrome : a case report and results single photon emission computed tomography and computer-assisted electroencephalographic analysis"Brain & Development. 23. 246-250 (2001)
• [Publications] H Oguni, et al.: "Severe myoclonic epilepsy in infants-a review based on the Tokyo Women's Medical University series of 84 cases"Brain & Development. 23. 736-748 (2001)
• [Publications] H Oguni, et al.: "Myoclonic-astatic epilepsy of early childhood-clinical and EEG analysis of myoclonic-astatic seizures, and discussions on the nosology of the syndrome"Brain & Development. 23. 757-764 (2001)
• [Publications] S Shirakawa, et al.: "A study of the effect of color photostimulation from a cathode-ray tube(CRT) display on photosensitive patients : The effect of alternating red-cyan flicker stimulation"Epilepsia. 42(7). 922-929 (2001)
• [Publications] M Funatsuka, et al.: "Study on photo-pattern sensitivity in patients with electronic screen gome-induced seizures(ESGS) : Effects of spatial resolution, brightness, and pattern movement"Epilepsia. 42(9). 1185-1197 (2001)
• [Publications] M Ueno, et al.: "Neurophysiological study of secondary synchronous occipito-frontopolar spikes in childhood"Clinical Neurophysiology. 112. 2106-2112 (2001)
• [Publications] Y Goto: "Clinical and molecular studies of mitochondrialdisease"J Inherit Metab Dis. 24. 181-188 (2001)
• [Publications] N Adachi, et al.: "Dentatorubral-pallidoluysian atrophy (DRPLA) presenting with psychosis"J Neuropsychitry Clin Neurosci. 13(2). 258-260 (2001)
• [Publications] Y Goto, et al.: "Mitochodrial DNA deletion and duplication in human disease and mouse model"Acta Myologica. 20. 110-114 (2001)
• [Publications] T Ohura, et al.: "Neonatal presentation of adult-onset type II citrullinemia"Hum Genet. 108. 87-90 (2001)
• [Publications] O Sakamoto, et al.: "A novel intronic mutation of the TAZ (G4.5) gene in a patient with Barth syndrome : creation of a 5'splice donor site with variant GC consensus and elongation of the upstream exon"Hum Genet. 109. 559-563 (2001)
• [Publications] K Haginoya, et al.: "Mechanism of tonic spasms in West syndrome viewed from ictal SPECT findings"Brain & Development. 23. 496-501 (2001)
• [Publications] Y Aoki, et al.: "A novel mutation in glial fibrillary acidic protein gene in a patient with Alexander disease"Neuroscience Letters. 312. 71-74 (2001)
• [Publications] H Date, et al.: "Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene"Nature Genetics. 29. 184-188 (2001)
• [Publications] A Okumura, et al.: "Five-year follow-up of patients with partial epilepsies in infancy"Pediatric Neurology. 24(4). 290-296 (2001)
• [Publications] K Watanabe, et al.: "Symptomatology of infantile spasms"Brain & Development. 23. 453-466 (2001)
• [Publications] A Okumura, et al.: "Clinico-electrical evolution in per-hypsarrythmic stage : toward prediction and prevention of West syndrome"Brain & Development. 23. 482-487 (2001)
• [Publications] A Okumura, et al.: "The timing of brain insults preterm infants who later developed West syndrome"Neuropediatrics. 32. 245-249 (2001)
• [Publications] H Akiyoshi, et al: "A novel SSCP varient (c.828G>A) within the M2 domain of the human neuronal nicotinic acetylcholine receptor alpha 4 subunit gene, CHRNA4"Human Genetics. 16(5)(online). (2000)
• [Publications] 兼子 直, 他: "てんかん・熱性けいれんの遺伝子解析"脳21. 4(3). 31-35 (2001)
• [Publications] 兼子 直: "てんかん遺伝子研究の現状と将来展望"実験医学. 19(17). 2289-2296 (2001)
• [Publications] 兼子 直, 他: "てんかんの分子病態"精神神経学雑誌. 103(9). 712-717 (2001)
• [Publications] 兼子 直, 他: "てんかんの分子医学"現代医療. 33(11). 2755-2760 (2001)
• [Publications] 佐野 輝: "遺伝性てんかん"最新精神医学. 6(6). 553-558 (2001)
• [Publications] 佐野 輝: "ミオクローヌスてんかんの分子遺伝学"分子精神医学. 1(4). 351-357 (2001)
• [Publications] 丸山幸一, 他: "欠神発作を主症状とした前頭葉てんかんの1例"脳と発達. 34(1). 72-76 (2002)
• [Publications] 奥村彰久, 他: "脳波異常を伴う熱性けいれんの取り扱いに関するアンケート調査"小児科臨床. 54(10). 1877-1882 (2001)
• [Publications] 渡辺一功: "てんかん症候群分類における最近の進歩"小児科. 42(11). 1754-1763 (2001)