Study of cerebellum disturbance by genetic approaches

• Project/Area Number: 26242085
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Basic / Social brain science
• Research Institution: Hiroshima University
• Principal Investigator: Kawakami Hideshi 広島大学, 原爆放射線医科学研究所, 教授 (70253060)
• Co-Investigator(Kenkyū-buntansha): 森野 豊之 広島大学, 原爆放射線医科学研究所, 准教授 (10397953) ; 大澤 亮介 広島大学, 原爆放射線医科学研究所, 助教 (20719356) ; 福士 雅也 広島大学, 医歯薬保健学研究科(医), 助教 (50313515) ; 山本 卓 広島大学, 理学研究科, 教授 (90244102) ; 丸山 博文 広島大学, 医歯薬保健学研究科(医), 教授 (90304443) ; 外丸 祐介 広島大学, 自然科学研究支援開発センター, 教授 (90309352) ; 平木 啓子 広島大学, 原爆放射線医科学研究所, 研究員 (10455397)
• Project Period (FY): 2014-06-27 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥44,330,000 (Direct Cost: ¥34,100,000、Indirect Cost: ¥10,230,000); Fiscal Year 2017: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000); Fiscal Year 2016: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000); Fiscal Year 2015: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000); Fiscal Year 2014: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
• Keywords: 脊髄小脳変性症 / Ca チャンネル / 脳神経疾患 / 遺伝子 / 神経科学 / 遺伝性脊髄小脳変性症

Outline of Final Research Achievements

We analyzed two Japanese families with autosomal dominant SCA using linkage analysis and exome sequencing, and identified CACNA1G, which encodes the calcium channel CaV3.1, as a new causative gene. Although most patients exhibited the pure form of cerebellar ataxia, two patients showed prominent resting tremor in addition to ataxia. CaV3.1 is classified as a low-threshold voltage-dependent calcium channel (T-type) . The mutation p.Arg1715His, identified in this study, was found to be located at S4 of repeat IV, the voltage sensor of the CaV3.1. Electrophysiological analyses revealed that the membrane potential dependency of the mutant CaV3.1 transfected into HEK293T cells shifted toward a positive potential
Our study also identifies Twinkle mutations as a cause of Perrault syndrome accompanied by neurologic features and expands the phenotypic spectrum of recessive disease caused by mutations in Twinkle.

Research Products

• [Journal Article] First report of a Japanese family with spinocerebellar ataxia type 10: The second report from Asia after a report from China (2017)
  • Author(s): Naito Hiroyuki、Takahashi Tetsuya、Kamada Masaki、Morino Hiroyuki、Yoshino Hiroyo、Hattori Nobutaka、Maruyama Hirofumi、Kawakami Hideshi、Matsumoto Masayasu
  • Journal Title: PLOS ONE Volume: 12 Issue: 5 Pages: 0177955-0177955
  • DOI: 10.1371/journal.pone.0177955
  • Peer Reviewed / Open Access
• [Journal Article] PLK1-mediated phosphorylation of WDR62/MCPH2 ensures proper mitotic spindle orientation (2017)
  • Author(s): Miyamoto Tatsuo、Akutsu Silvia Natsuko、Fukumitsu Akihiro、Morino Hiroyuki、Masatsuna Yoshinori、Hosoba Kosuke、Kawakami Hideshi、Yamamoto Takashi、Shimizu Kenji、Ohashi Hirofumi、Matsuura Shinya
  • Journal Title: Human Molecular Genetics Volume: 26 Issue: 22 Pages: 4429-4440
  • DOI: 10.1093/hmg/ddx330
  • Peer Reviewed
• [Journal Article] Novel compound heterozygous mutations in the PARK2 gene identified in a Chinese pedigree with early-onset Parkinson's disease (2017)
  • Author(s): Shi Yingying、Kawakami Hideshi、Zang Weizhou、Li Gang、Zhang Jiewen、Xu Changshui
  • Journal Title: Brain and Behavior Volume: 8 Issue: 1
  • DOI: 10.1002/brb3.901
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Vulnerability of Purkinje Cells Generated from Spinocerebellar Ataxia Type 6 Patient-Derived iPSCs. (2016)
  • Author(s): Ishida Y, Kawakami H, Kitajima H, Nishiyama A, Sasai Y, Inoue H, Muguruma K.
  • Journal Title: Cell Rep Volume: 17 Issue: 6 Pages: 1482-1490
  • DOI: 10.1016/j.celrep.2016.10.026
  • NAID: 120006223645
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A mutation in the low voltage -gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia. (2015)
  • Author(s): Morino H., Matsuda Y., Muguruma K., Miyamoto R., Ohsawa R., Ohtake T., Otobe R., Watanabe M., Maruyama H., Hashimoto K., Kawakami H.
  • Journal Title: Molecular Brain Volume: 8 Issue: 1 Pages: 1-9
  • DOI: 10.1186/s13041-015-0180-4
  • Peer Reviewed / Open Access
• [Journal Article] Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. (2015)
  • Author(s): Muguruma K, et al.
  • Journal Title: Cell Reports Volume: 10 Issue: 4 Pages: 537-550
  • DOI: 10.1016/j.celrep.2014.12.051
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features. (2014)
  • Author(s): Morino H
  • Journal Title: Neurology Volume: 83 Issue: 22 Pages: 2054-2061
  • DOI: 10.1212/wnl.0000000000001036
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Perrault症候群の原因遺伝子C10orf2の変異によるmtDNA維持機構の障害 (2014)
  • Author(s): 森野豊之、川上秀史
  • Organizer: 日本人類遺伝学会第59回大会
  • Place of Presentation: 東京
  • Year and Date: 2014-11-20 – 2014-11-23
• [Patent(Industrial Property Rights)] 伝子改変非ヒト動物及び脊髄小脳変性症の治療薬又は予防薬のスクリーニング法 (2018)
  • Inventor(s): 川上秀史、森野豊之、松田由喜子
  • Industrial Property Rights Holder: 広島大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-031706
  • Filing Date: 2018