Identification of the novel genes responsible for hereditary spastic paraplegias

• Project/Area Number: 23591253
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Jichi Medical University
• Principal Investigator: SHIMAZAKI HARUO 自治医科大学, 医学部, 講師 (30316517)
• Co-Investigator(Kenkyū-buntansha): TAKIYAMA Yoshihisa 山梨大学, 医学部, 教授 (00245052)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 遺伝性痙性対麻痺 / 連鎖解析 / エクソーム解析 / SPG55 / C12orf65遺伝子 / LYST遺伝子 / モデル動物 / TALEN / ATM遺伝子 / 遺伝性脊髄小脳変性症 / Chediak-Higashi症候群 / C12orf65 / ミトコンドリアDNA翻訳

Research Abstract

We attempted to identify the causative gene mutations for the four families that have suffered from autosomal recessive hereditary spastic paraplegias (ARHSP). Using homozygosity mapping and exome sequencing, we could isolate a homozygous nonsense mutation in the responsible gene, C12orf65, in one complicated ARHSP family. HUGO assigned this type of ARHSP as SPG55. We also detected a novel homozygous missense mutation of the LYST gene in another complicated ARHSP family.
We also have investigated the responsive genes in two pure ARHSP families by homozygosity mapping and exome sequencing. We identified two homozygous single nucleotide variants of two genes in the two families. We are verifying whether these variants are the causative mutations or not.

Research Products

• [Journal Article] Autosomal recessive complicated spastic paraplegia with a novel lysosomal trafficking regulator gene mutation. (2014)
  • Author(s): Shimazaki H, et al.
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 85 Issue: 9 Pages: 1-5
  • DOI: 10.1136/jnnp-2013-306981
  • Peer Reviewed
• [Journal Article] 常染色体劣性遺伝性痙性対麻痺 (2014)
  • Author(s): 嶋崎晴雄
  • Journal Title: 日本臨床別冊神経症候群II-その他の神経疾患を含めて- Volume: 第2版 Pages: 438-442
• [Journal Article] 常染色体劣性遺伝性痙性対麻痺 (2014)
  • Author(s): 嶋崎晴雄
  • Journal Title: 日本臨床別冊：神経症候群II-その他の神経疾患を含めて- Volume: 72 Pages: 438-442
• [Journal Article] Middle cerebellar peduncles and pontine T2 hypointensities in ARSACS (2013)
  • Author(s): Shimazaki H, Takiyama Y, Honda J, Sakoe K, Namekawa M, Tsugawa J, Tsuboi Y, Suzuki C, Baba M, Nakano I
  • Journal Title: J Neuroimaging Volume: 23(1) Issue: 1 Pages: 82-85
  • DOI: 10.1111/j.1552-6569.2011.00647.x
  • Peer Reviewed
• [Journal Article] 視神経萎縮,末梢神経障害を伴う常染色体劣性遺伝性痙性対麻痺(SPG55).特集/脊髄小脳変性症の研究の進歩 (2013)
  • Author(s): 嶋崎晴雄
  • Journal Title: 神経内科 Volume: 78(3) Pages: 283-9
• [Journal Article] Mutations in the mitochondrial gene C12ORF65 lead to syndromic autosomal recessive intellectual disability and show genotype phenotype correlation. (2013)
  • Author(s): Buchert R, Shimazaki H, et al.
  • Journal Title: Eur J Med Genet Volume: 56 Issue: 11 Pages: 599-602
  • DOI: 10.1016/j.ejmg.2013.09.010
  • Peer Reviewed
• [Journal Article] 視神経萎縮,末梢神経障害を伴う常染色体劣性遺伝性痙性対麻痺(SPG55) (2013)
  • Author(s): 嶋崎晴雄
  • Journal Title: 神経内科 Volume: 78 Pages: 283-289
• [Journal Article] Novel compound heterozygous mutations of the SACS gene in autosomal recessive spastic ataxia of Charlevoix-Saguenay (2012)
  • Author(s): Haga R, Miki Y, Funamizu Y, Kon T, Suzuki C, Ueno T, Nishijima H, Arai A, Tomiyama M, Shimazaki H, Takiyama Y, Baba M
  • Journal Title: Clin Neurol Neurosurg Volume: 114(6) Issue: 6 Pages: 746-747
  • DOI: 10.1016/j.clineuro.2011.12.019
  • Peer Reviewed
• [Journal Article] A novel adult case of juvenile-onset Alexander disease: complete remission of neurological symptoms for over 12 years, despite insidiously progressive cervicomedullary atrophy (2012)
  • Author(s): Namekawa M, Shimazaki H, et al.
  • Journal Title: Neurol Sci Volume: 33 Issue: 6 Pages: 1389-1392
  • DOI: 10.1007/s10072-011-0902-z
  • Peer Reviewed
• [Journal Article] A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55) (2012)
  • Author(s): Shimazaki H, Takiyama Y, Ishiura H, Sakai C, Matsushima Y, Hatakeyama H, Honda J, Sakoe K, Naoi T, Namekawa M, Fukuda Y, Takahashi Y, Goto J, Tsuji S, Goto Y, Nakano I
  • Journal Title: J Med Genet Volume: 49(12) Issue: 12 Pages: 777-84
  • DOI: 10.1136/jmedgenet-2012-101212
  • Peer Reviewed
• [Journal Article] 脊髄小脳変性症,多系統萎縮症,進行性核上性麻痺.疾患概念の変遷と,脊髄疾患ならびにパーキンソン病との鑑別 (2012)
  • Author(s): 嶋崎晴雄,中野今治
  • Journal Title: 脊髄外科SPINAL SURGERY Volume: 26(3) Pages: 278-283
• [Journal Article] 常染色体劣性遺伝性痙性対麻痺の臨床-SPG11, ARSACSを中心に-,特集/遺伝性痙性対麻痺-update (2011)
  • Author(s): 嶋崎晴雄
  • Journal Title: 神経内科 Volume: 74(2) Pages: 127-134
• [Journal Article] 遺伝性痙性対麻痺の疫学:JASPAC.特集/遺伝性痙性対麻痺-update (2011)
  • Author(s): 瀧山嘉久,石浦浩之,嶋崎晴雄,辻省次,西澤正豊
  • Journal Title: 神経内科 Volume: 74(2) Pages: 141-145
• [Journal Article] 当院におけるPosterior reversible encephalopathy syndrome (PRES) 12症例の検討． (2011)
  • Author(s): 中原圭一，嶋崎晴雄ら
  • Journal Title: 日本神経救急学会雑誌 Volume: 23巻 Pages: 24-28
  • Peer Reviewed
• [Journal Article] 一級症状（K. Schneider）を呈した抗NMDA受容体脳炎の一例． (2011)
  • Author(s): 松本卓也，嶋崎晴雄ら
  • Journal Title: 精神科治療学 Volume: 26巻 Pages: 1035-1043
  • Peer Reviewed
• [Presentation] 常染色体劣性遺伝が疑われた遺伝痙性対麻痺症例のexome解析 (2013)
  • Author(s): 石浦浩之,高紀信、嶋崎晴雄、三井純、高橋祐二、吉村淳、土井晃一郎、森下真一、後藤順、瀧山嘉久、辻省次、JASPAC
  • Organizer: 日本人類遺伝学会第58回大会
  • Place of Presentation: 仙台
  • Year and Date: 2013-11-22
• [Presentation] Novel ATM mutation in autosomal recessive late-onset cerebellar ataxia with neuropathy (2013)
  • Author(s): Shimazaki H, Sugaya R, Honda J, Meguro A, Nakano I
  • Organizer: American Society of Human Genetics 2013 Annual Meeting
  • Place of Presentation: Boston
  • Year and Date: 2013-10-24
• [Presentation] 小脳失調,末梢神経障害を呈した常染色体劣性遺伝性痙性対麻痺家系の遺伝子解析 (2013)
  • Author(s): 嶋崎晴雄,本多純子,直井為任,滑川道人,石浦浩之,福田陽子,高橋祐二,後藤順,辻省次,矢崎正英,中村勝哉,吉田邦広,池田修一,瀧山嘉久,中野今治
  • Organizer: 第54回日本神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2013-05-31
• [Presentation] Adult Chediak-Higashi syndrome presenting as spastic paraplegia, cerebellar ataxia and neuropathy (2013)
  • Author(s): Shimazaki H, Takiyama Y, Ishiura H, Tsuji S, Yazaki M, Nakano I
  • Organizer: American Academy of Neurology 65^<th> Annual Meeting
  • Place of Presentation: San Diego
  • Year and Date: 2013-05-21
• [Presentation] 小脳失調，末梢神経障害を呈した常染色体劣性遺伝性痙性対麻痺家系の遺伝子解析 (2013)
  • Author(s): 嶋崎晴雄ら．
  • Organizer: 平成24年度運動失調症の病態解明と治療法開発に関する研究班会議
  • Place of Presentation: 東京
• [Presentation] Adult Chediak-Higashi syndrome presenting as spastic paraplegia, cerebellar ataxia and neuropathy (2013)
  • Author(s): Shimazaki H, et.al.
  • Organizer: American Academy of Neurology 65th Annual Meeting
  • Place of Presentation: San Diego
• [Presentation] Homozygous nonsense mutations of C12orf65 gene in patients with spastic paraplegia, optic atrophy and neuropathy (SPG55) (2012)
  • Author(s): Shimazaki H, Takiyama Y, Ishiura H, Tsuji S, Goto Y, Nakano I
  • Organizer: 2012 Annual Meeting of American Neurological Association
  • Place of Presentation: Boston
  • Year and Date: 2012-10-07
• [Presentation] 視神経萎縮,末梢神経障害を伴う遺伝性痙性対麻痺の原因遺伝子同定 (2012)
  • Author(s): 嶋崎晴雄,石浦浩之,福田陽子,本多純子,迫江公己,太田京子,直井為任,滑川道人,高橋祐二,後藤順,辻省次,後藤雄一,瀧山嘉久,中野今治
  • Organizer: 第53回日本神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-05-23
• [Presentation] 遺伝性痙性対麻痺の新規原因遺伝子同定とその機能解析 (2012)
  • Author(s): 嶋崎晴雄ら．
  • Organizer: 新学術｢ゲノム支援｣拡大班会議
  • Place of Presentation: 御殿場
• [Presentation] 視神経萎縮, 末梢神経障害を伴う遺伝性痙性対麻痺の原因遺伝子同定． (2012)
  • Author(s): 嶋崎晴雄ら．
  • Organizer: 平成23年度運動失調症の病態解明と治療法開発に関する研究班会議
  • Place of Presentation: 東京
• [Presentation] 視神経萎縮,末梢神経障害を伴う遺伝性痙性対麻痺症例の臨床像と,原因遺伝子検索 (2011)
  • Author(s): 嶋崎晴雄,石浦浩之,福田陽子,本多純子,太田京子,直井為任,滑川道人,迫江公己,高橋祐二,後藤順,辻省次,瀧山嘉久,中野今治
  • Organizer: 第52回日本神経学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-20
• [Presentation] SPG4遺伝子産物spastinの機能解析 (2011)
  • Author(s): 迫江公己,嶋崎晴雄,滑川道人,直井為任,本多純子,瀧山嘉久,中野今治
  • Organizer: 第52回日本神経学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-18
• [Presentation] 視神経萎縮,末梢神経障害を伴う遺伝性痙性対麻痺症例の臨床像と, 原因遺伝子検索. (2011)
  • Author(s): 嶋崎晴雄ら．
  • Organizer: 第52回日本神経学会総会
  • Place of Presentation: 名古屋
• [Presentation] Diffuse reduction of cerebral blood flow, cognitive impairment and depressive mood in sporadic SCD cases with APTX and SETX mutations. (2011)
  • Author(s): Ikeda M, Shimazaki H, et al.
  • Organizer: 4th International Symposium, Society for Research on the Cerebellum.
  • Place of Presentation: Tokyo
• [Presentation] 小脳失調，末梢神経障害を呈した常染色体劣性遺伝性痙性対麻痺家系の遺伝子解析．
  • Author(s): 嶋崎晴雄ら．
  • Organizer: 第54回日本神経学会総会
  • Place of Presentation: 東京
• [Presentation] 常染色体劣性遺伝性痙性対麻痺の新規原因遺伝子探索
  • Author(s): 嶋崎晴雄ら．
  • Organizer: 新学術｢ゲノム支援｣2013年度拡大班会議
  • Place of Presentation: 神戸
• [Presentation] Novel ATM mutation in autosomal recessive late-onset cerebellar ataxia with neuropathy.
  • Author(s): Shimazaki, H. et al.
  • Organizer: American Society of Human Genetics 2013 Annual Meeting
  • Place of Presentation: Boston
• [Presentation] 常染色体劣性遺伝性痙性対麻痺の新規原因遺伝子探索
  • Author(s): 嶋崎晴雄ら．
  • Organizer: 平成25年度運動失調症の病態解明と治療法開発に関する研究班会議
  • Place of Presentation: 東京
• [Book] Autosomal recessive spastic ataxia of Charlevoix-Saguenay : clinical, radiological and epidemiological aspects. Spinocerebellar Ataxia(Edited by Prof. Jose Gazulla) (2012)
  • Author(s): Shimazaki H and Takiyama Y
  • Publisher: InTech, Rijeka, Croatia(ISBN:978-953-51-0542-8)(査読有)
• [Book] Spinocerebellar Ataxia (2012)
  • Author(s): Shimazaki H and Takiyama Y.
  • Total Pages: 172
  • Publisher: InTech
• [Book] Clinical aspects of anti-NMDA receptor encephalitis. In Pathogenesis of encephalitis (2011)
  • Author(s): Shimazaki H.
  • Total Pages: 344
  • Publisher: InTech, Rijeka, Croatia.