Identification of novel gene of spinocerebellar ataxia for new target of therapy.

• Project/Area Number: 17K17772
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology; Medical genome science
• Research Institution: University of Yamanashi
• Principal Investigator: KOH Kishin 山梨大学, 大学院総合研究部, 助教 (00622557)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 脊髄小脳変性 / 遺伝性痙性対麻痺 / シャルコーマリートゥース病 / 脊髄小脳変性症 / 脳神経疾患

Outline of Final Research Achievements

I had tried to find novel genes of spinocerebellar ataxia in our eight spinocerebellara ataxia families. I used whole-exome analysis, whole-genome analysis, and linkage analysis. I had diagnosed two families among these eight families. I had screened two genes among our data-set. I had found one and two more families with these causative genes. These genes were reported by other teams. That indicated that these genes were truly causative genes. Thereafter, I collected precise clinical data of patients with these gene mutations. I had already reported one of them. I had already submitted another one. I would continue analyzing of remained six families with spinocerebellar ataxia families.

Academic Significance and Societal Importance of the Research Achievements

遺伝性脊髄小脳変性症は未だに根治療法がなく、厚生労働省の指定難病となっている難治な疾患である。治療標的を見出すためにも病態の解明が不可欠であり、小脳萎縮をきたす機序の解明のために原因遺伝子を同定することは必須である。本研究開始時点では同定されていなかった新規の原因遺伝子の家系をそれぞれ2家系、3家系同定することができた。また臨床症状の集積から変異と臨床症状の関連性が今後さらに明らかとなり、治療標的の同定、治療法の開発に寄与するものと考えられる。

Research Products

• [Journal Article] Clinical and Genetic Study of the First Japanese FTDP-17 Patient with a Mutation of +3 in Intron 10 in the <i>MAPT</i> Gene (2019)
  • Author(s): Nan H, Takaki R, Shimozono K, Ichinose Y, Koh K, Takiyama Y.
  • Journal Title: Internal Medicine Volume: 58 Issue: 16 Pages: 2397-2400
  • DOI: 10.2169/internalmedicine.2761-19
  • NAID: 130007690145
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-08-15
  • Peer Reviewed
• [Journal Article] Exome Sequencing Reveals a Novel Homozygous Frameshift Mutation in the <i>CYP7B1</i> Gene in a Japanese Patient with SPG5 (2019)
  • Author(s): Nan H, Shimozono K, Ichinose Y, Tsuchiya M, Koh K, Hiraide M, Takiyama Y
  • Journal Title: Internal Medicine Volume: 58 Issue: 5 Pages: 719-722
  • DOI: 10.2169/internalmedicine.1839-18
  • NAID: 130007606127
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-03-01
  • Peer Reviewed
• [Journal Article] Non-convulsive status epilepticus associated with neuronal intranuclear inclusion disease: A case report and literature review. (2019)
  • Author(s): Shindo K, Tsuchiya M, Hata T, Ichinose Y, Koh K, Sone J, Nagasaka T, Sobue G, Takiyama Y.
  • Journal Title: Epilepsy Behav Case Rep. Volume: 11 Pages: 103-106
  • DOI: 10.1016/j.ebcr.2019.01.007
  • Peer Reviewed
• [Journal Article] A Japanese family with a novel nonsense mutation in the spastin gene associated with both cerebellar ataxia and cognitive impairment (2019)
  • Author(s): Tsuchiya M, Koh K, Ishida A, Ichinose Y, Shindo K, Takiyama Y
  • Journal Title: J Neurol Sci Volume: 397 Pages: 114-116
  • DOI: 10.1016/j.jns.2018.12.025
  • Peer Reviewed
• [Journal Article] Neuroimaging, genetic, and enzymatic study in a Japanese family with a GBA gross deletion. (2019)
  • Author(s): Ichinose Y, Ishiura H, Tanaka M, Yoshimura J, Doi K, Umeda T, Yamauchi H, Tsuchiya M, Koh K, Yamashiro N, Mitsui J, Goto J, Onishi H, Ohtsuka T, Shindo K, Morishita S, Tsuji S, Takiyama Y.
  • Journal Title: Parkinsonism Relat Disord. Volume: - Pages: 57-63
  • DOI: 10.1016/j.parkreldis.2018.11.028
  • Peer Reviewed / Open Access
• [Journal Article] A novel homozygous mutation of the TFG gene in a patient with early onset spastic paraplegia and later onset sensorimotor polyneuropathy (2019)
  • Author(s): Miyabayashi T, Ochiai T, Suzuki N, Aoki M, Inui T, Okubo Y, Sato R, Togashi N, Takashima H, Ishiura H, Tsuji S, Koh K, Takiyama Y, Haginoya K
  • Journal Title: J Hum Genet Volume: 64 Issue: 2 Pages: 171-176
  • DOI: 10.1038/s10038-018-0538-4
  • Peer Reviewed
• [Journal Article] Novel GARS mutation presenting as autosomal dominant intermediate Charcot-Marie-Tooth disease. (2019)
  • Author(s): Nan H, Takaki R, Hata T, Ichinose Y, Tsuchiya M, Koh K, Takiyama Y.
  • Journal Title: J Peripher Nerv Syst. Volume: 24 Issue: 1 Pages: 156-160
  • DOI: 10.1111/jns.12289
  • Peer Reviewed
• [Journal Article] Decreasing 123I-ioflupane SPECT accumulation and 123I-MIBG myocardial scintigraphy uptake in a patient with a novel homozygous mutation in the ZFYVE26 gene (2019)
  • Author(s): Koh K, Tsuchiya M, Nagasaka T, Shindo K, Takiyama Y
  • Journal Title: Neurol Sci Volume: 40 Issue: 2 Pages: 429-431
  • DOI: 10.1007/s10072-018-3603-z
  • Peer Reviewed
• [Journal Article] PLA2G6-associated neurodegeneration presenting as a complicated form of hereditary spastic paraplegia (2019)
  • Author(s): Koh K, Ichinose Y, Ishiura H, Nan H, Mitsui J, Takahashi J, Sato W, Itoh Y, Hoshino K, Tsuji S, Takiyama Y, Japan Spastic Paraplegia Research Consortium
  • Journal Title: J Hum Genet Volume: 64 Issue: 1 Pages: 55-59
  • DOI: 10.1038/s10038-018-0519-7
  • Peer Reviewed
• [Journal Article] JASPAC: Japan Spastic Paraplegia Research Consortium (2019)
  • Author(s): Koh K, Ishiura H, Tsuji S, Takiyama Y
  • Journal Title: Brain Sci Volume: 8 Issue: 8 Pages: 153-153
  • DOI: 10.3390/brainsci8080153
  • Peer Reviewed / Open Access
• [Journal Article] Novel <i>SPG11</i> Mutations in a Patient with Symptoms Mimicking Multiple Sclerosis (2018)
  • Author(s): Mukai M, Koh K, Ohnuki Y, Nagata E, Takiyama Y, Takizawa S
  • Journal Title: Internal Medicine Volume: 57 Issue: 21 Pages: 3183-3186
  • DOI: 10.2169/internalmedicine.0976-18
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2018-11-01
  • Peer Reviewed
• [Journal Article] Novel mutations in the ALDH18A1 gene in complicated hereditary spastic paraplegia with cerebellar ataxia and cognitive impairment (2018)
  • Author(s): Koh K, Ishiura H, Beppu M, Shimazaki H, Ichinose Y, Mitsui J, Kuwabara S, Tsuji S, Takiyama Y, Japan Spastic Paraplegia Research Consortium
  • Journal Title: J Hum Genet Volume: 63 Issue: 9 Pages: 1009-1013
  • DOI: 10.1038/s10038-018-0477-0
  • Peer Reviewed
• [Journal Article] Novel SLC20A2 mutation in primary familial brain calcification with disturbance of sustained phonation and orofacial apraxia (2018)
  • Author(s): Nan Haitian、Takaki Ryusuke、Ichinose Yuta、Tsuchiya Mai、Koh Kishin、Hanyu Shuji、Shindo Kazumasa、Takiyama Yoshihisa
  • Journal Title: Journal of the Neurological Sciences Volume: 390 Pages: 1-3
  • DOI: 10.1016/j.jns.2018.03.031
  • Peer Reviewed
• [Journal Article] Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy (2018)
  • Author(s): Ishiura Hiroyuki、Doi Koichiro、Mitsui Jun、Yoshimura Jun、Matsukawa Miho Kawabe、Takahashi Yuji、Date Hidetoshi、Matsukawa Takashi、Shimizu Jun、Koh Kishin、Takiyama Yoshihisa、Goto Jun、Morishita Shinichi、Tsuji Shoji
  • Journal Title: Nature Genetics Volume: 50 Issue: 4 Pages: 581-590
  • DOI: 10.1038/s41588-018-0067-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sympathetic neurograms showing characteristics of both muscle and skin sympathetic nerve activity in a case with pure autonomic failure (2018)
  • Author(s): Shindo Kazumasa、Satake Akane、Kurita Naofumi、Sato Toko、Tsuchiya Mai、Ichinose Yuta、Hata Takanori、Koh Kishin、Nagasaka Takamura、Takiyama Yoshihisa
  • Journal Title: Clinical Autonomic Research Volume: - Issue: 3 Pages: 347-349
  • DOI: 10.1007/s10286-017-0497-4
  • Peer Reviewed
• [Journal Article] Pre- and postganglionic vasomotor dysfunction causes distal limb coldness in multiple system atrophy (2017)
  • Author(s): Shindo Kazumasa、Tsuchiya Mai、Ichinose Yuta、Koh Kishin、Hata Takanori、Yamashiro Nobuo、Kobayashi Fumikazu、Nagasaka Takamura、Takiyama Yoshihisa
  • Journal Title: Journal of the Neurological Sciences Volume: 380 Pages: 191-195
  • DOI: 10.1016/j.jns.2017.07.018
  • Peer Reviewed
• [Presentation] A new method to detect potential causative genes for spastic paraplegia utilizing aggregate data of whole exome sequencing. (2018)
  • Author(s): Tanaka M, Koh K, Takiyama Y, Tsuji S
  • Organizer: The 70th Annual Meeting of the American Academy of Neurology
  • Int'l Joint Research
• [Presentation] Clinical and genetic analysis of three Japanese SPG3A families. (2018)
  • Author(s): Takegami N, Ishiura H, Iwata NK, Murai H, Yasaka K, Takuma H, Tamaoka A, Koh K, Takiyama Y, Tsuji S, Toda T, and Goto J
  • Organizer: The 59th Annual Meeting of the Japanese Society of Neurology
• [Presentation] 痙性対麻痺に認知機能低下と小脳性運動失調を合併したSPG4一家系の臨床・遺伝学的検討 (2018)
  • Author(s): 土屋 舞、高 紀信、一瀬佑太、瀧山嘉久
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] ATP13A2遺伝子のp.Ala885Asp (c.2654C>A) 変異を認めた遺伝性痙性対麻痺の1家系 (2018)
  • Author(s): 小竹泰子、高 紀信、瀧山嘉久、石浦浩之、辻 省次、吉田光宏
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] Japan Spastic Paraplegia Research Consortium: 分かったこと、分からないこと (2018)
  • Author(s): 高 紀信、石浦浩之、一瀬佑太、田中真生、三井 純、JASPAC、辻 省次、瀧山嘉久
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] JASPAC: 遺伝性痙性対麻痺へのITB療法 (2018)
  • Author(s): 一瀬佑太、高 紀信、石浦浩之、戸田達史、辻 省次、瀧山嘉久
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] Co-aggregation of amyloid-beta and transthyretin in sporadic inclusion body myositis. (2018)
  • Author(s): Nagasaka T, Hata T, Sato T, Satake A, Kurita T, Tsuchiya M, Koh K, Ichinose Y, Shindo K, Takiyama Y
  • Organizer: The 59th Annual Meeting of the Japanese Society of Neurology
• [Presentation] 多系統萎縮症患者における皮膚交感神経活動と年齢、罹病期間との関連性の検討. (2018)
  • Author(s): 新藤和雅、佐藤統子、栗田尚史、佐竹紅音、土屋 舞、一瀬佑太、羽田貴礼、高 紀信、長坂高村、瀧山嘉久
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] パーキンソン病診断におけるイオフルパンSPECTとMIBG心筋シンチグラフィーの有用性 (2018)
  • Author(s): 村田博朗、土屋 舞、梅田貴子、高 紀信、羽田貴礼、長坂高村、新藤和雅、大西 洋、瀧山嘉久
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] PLA2G6遺伝子変異は遺伝性痙性対麻痺を引き起こす (2018)
  • Author(s): 高 紀信、一瀬佑太、石浦浩之、三井 純、高橋純哉、佐藤和貴郎、伊藤義彰、星野恭子、JASPAC、辻 省次、瀧山嘉久
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] PLA2G6遺伝子にホモ接合性p.R635Q変異を認めた遺伝性痙性対麻痺の一症例. (2018)
  • Author(s): 長谷川樹、木村裕子、三野俊和、竹内潤、田村暁子、武田景俊、逢坂麻由子、高紀信、小坂理、安部貴人、瀧山嘉久、伊藤義彰
  • Organizer: 第111回日本神経学会近畿地方会
• [Presentation] VPS13D遺伝子変異による複合型遺伝性痙性対麻痺の44歳女性例 (2018)
  • Author(s): 高 紀信、佐竹紅音、土屋舞、高木隆助、長坂高村、新藤和雅、瀧山嘉久
  • Organizer: 第226回日本神経学会関東・甲信越地方会
• [Presentation] 家系内に末梢神経障害の混在を認めた遺伝性痙性対麻痺の36歳女性例 (2018)
  • Author(s): 高木隆助、高 紀信、石浦浩之、羽生修二、土屋 舞、一瀬佑太、新藤和雅、辻 省次、瀧山嘉久
  • Organizer: 第26回Nagano Neurology Conference
• [Presentation] 遺伝性脊髄小脳変性症の原因遺伝子探索. (2018)
  • Author(s): 高 紀信、瀧山嘉久
  • Organizer: H.30年度先端ゲノム支援拡大班会議
• [Presentation] A New Method to Detect Potential Causative Genes for Spastic Paraplegia Utilizing Aggregate Data of Whole Exome Sequencing (2018)
  • Author(s): Masaki Tanaka, Hiroyuki Ishiura, Jun Mitsui, Kishin Koh, Yuta Ichinose, Yoshihisa Takiyama, Shoji Tsuji
  • Organizer: American Academy of Neurology Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] Dopamine transporter imaging and glucocerebrosidase activity in parkinson’s disease patients with a heterozygous gross deletion mutation in gba in a japanese family (2017)
  • Author(s): Y Ichinose, H Ishiura, M Tanaka, T Umeda, H Yamauchi, M Tsuchiya, K Koh, N Yamashiro, T Nagasaka, Y Omiya, J Mitsui, J Goto, T Ohtsuka, H Onishi, S Kazumasa, S Tsuji, Y Takiyama
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] Clinical characteristics and detailed haplotype analysis of patients with SCA36 in Japan (2017)
  • Author(s): K Koh, H Ishiura, Y Ichikawa, T Matsukawa, J Goto, J Mitsui, Y Takahashi, M Kawabe Matsukawa, K Doi, J Yoshimura, M Namekawa, S Morishita, T Ogawa, Y Sunada, H Kurisaki, K Hasegawa, S Tsuji, Y Takiyama
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] Genetic analysis of a large single family with patients with spastic paraplegia and those with neuropathy (2017)
  • Author(s): Kishin Koh, Ryusuke Takaki, Mai Tsuchiya, Yuta Ichinose, Hiroyuki Ishiura, Shuji Hanyu, Shoji Tsuji, Yoshihisa Takiyama
  • Organizer: 日本人類遺伝学会第62回大会