常染色体優性遺伝性パーキンソン病の遺伝子解析･新規原因遺伝子同定

• Project/Area Number: 25461292
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Juntendo University
• Principal Investigator: 富山 弘幸 順天堂大学, 医学部, 准教授 (20515069)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Discontinued (Fiscal Year 2014)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 常染色体優性遺伝性パーキンソン病 / 新規責任遺伝子同定 / 遺伝子変異解析 / 臨床的特徴 / 国際情報交流 / パーキンソン病 / 遺伝 / 遺伝子解析

Outline of Annual Research Achievements

常染色体優性遺伝性パーキンソン病(ADPD)の責任遺伝子として1997年以降SNCAとLRRK2などが同定されているが，いまだADPDの全体像は不明である．そのため，本研究ではADPDの全貌を明らかにし，その分子遺伝学的知見から病態の解明に繋げていくことを目標とした．対象として本年度まで遺伝子バンクの構築を継続し，450を超えるADPD家系の解析を進めてきた．昨年度まで，SCA2のCAG繰り返し配列 (ポリグルタミンをコード)の中間伸長がADPDの2.3%を占める一方，他の主なポリグルタミン病の伸長は認めないことが判明した．さらにこの知見を世界的大規模解析に繋げ，結果を国際誌に発表した．また，GBA変異の大規模解析により，GBAのヘテロ変異が日本のADPDの実に25.9%を占めることが判明し，孤発性のみならず家族性特にADPDの発症に強く関与する遺伝的因子であると考えられた．
これらの世界的にも新しい知見を国際誌に発表し，ADPDの全貌を明らかにする上での本研究の成果を共有するとともに，ADPDの遺伝子解析スクリーニングの際にはSNCAの重複変異，LRRK2の変異のhot spotに加えGBAの点変異やSCA2のCAG繰り返し配列の変異解析も十分に考慮されるべきという指針を示すことができた．さらに，これまで当施設での診療，遺伝子バンク構築の過程においてADPDの1大家系を見出すことができていたが，研究代表者らは本研究で作成した同意書のもと発症者・非発症者の採血および研究協力の同意を得て，家系情報の収集，詳細な診察記録など現地調査を行った．そして本年度には本家系より新規責任遺伝子CHCHD2の同定を報告できた．また遺伝子バンクの他の家系からも本遺伝子変異が認められ，同様に書面で同意を得て非発症者も含む遺伝的解析，家系情報の収集，詳細な診察など現地調査も行い，CHCHD2変異をもつ家系・患者群の遺伝学的，臨床的特徴を評価できた．これらのことは，本研究の大きな目標の達成に繋がる成果となった．

Research Products

• [Journal Article] CHCHD2 mutations in autosomal dominant late-onset Parkinson’s disease: a genome-wide linkage and sequencing study. (2015)
  • Author(s): Funayama M, Ohe K, Amo T, Furuya N, Yamaguchi J, Saiki S, Yuanzhe L, Ogaki K, Ando M, Yoshinon H, Tomiyama H, Nishioka K, Hasegawa K, Saiki H, Satake W, Mogushi K, Sasaki R, Kokubo Y, Kuzuhara S, Toda T, Mizuno Y, Uchiyama Y, Ohno K, Hattori N.
  • Journal Title: Lancet Neurol Volume: 14 Issue: 3 Pages: 274-282
  • DOI: 10.1016/s1474-4422(14)70266-2
  • Peer Reviewed / Open Access
• [Journal Article] ABCG2 variant has opposing effects on onset ages of Parkinson's disease and gout. (2015)
  • Author(s): Matsuo H, Tomiyama H, Satake W, Chiba T, Onoue H, Kawamura Y, Nakayama A, ShimizuS, Sakiyama M, Funayama M, Nishioka K, Shimizu T, Kaida K, Kamakura K, Toda T, Hattori N, ShinomiyaN.
  • Journal Title: Ann Clin Transl Neurol Volume: 2 Issue: 3 Pages: 302-306
  • DOI: 10.1002/acn3.167
  • Peer Reviewed / Open Access
• [Journal Article] Familial Parkinson's disease/parkinsonism.(Editorial) (2015)
  • Author(s): Tomiyama H, Lesage S, Tan EK, Jeon BS.
  • Journal Title: Biomed Res Int. Volume: 2015 Pages: 736915-736915
  • DOI: 10.1155/2015/736915
  • Open Access
• [Journal Article] Large Scale Assessment of Polyglutamine Repeat Expansions in Parkinson Disease (2015)
  • Author(s): Lisa Y Wang, Jan O. Aasly, Grazia Annesi, Soraya Bardien, Maria Bozi, Alexis Brice, Jonathan Carr, Sun Ju Chung, Carl Clarke, David Crosiers, Angela Deutschlaender, Gertrud Eckstein, Matthew Farrer, et al.
  • Journal Title: Neurology Volume: (in press)
  • Peer Reviewed
• [Journal Article] Clinicogenetic study of GBA mutations in patients with familial Parkinson's disease. (2014)
  • Author(s): Li Y, Sekine T, Funayama M, Li L, Yoshino H, Nishioka K, Tomiyama H, Hattori N
  • Journal Title: Neurobiol Aging. Volume: 35 Issue: 4 Pages: 935.e3-935.e8
  • DOI: 10.1016/j.neurobiolaging.2013.09.019
  • Peer Reviewed
• [Journal Article] The evaluation of polyglutamine repeats in autosomal dominant Parkinson's disease. (2014)
  • Author(s): Yamashita C, Tomiyama H, Funayama M, Inamizu S, Ando M, Li Y, Yoshino H, Araki T, Ichikawa T, Ehara Y, Ishikawa K, Mizusawa H, Hattori N.
  • Journal Title: Neurobiol Aging. Volume: 35 Issue: 7 Pages: 1779.e17-1779.e21
  • DOI: 10.1016/j.neurobiolaging.2014.01.022
  • Peer Reviewed / Open Access
• [Journal Article] A preliminary diffusional kurtosis imaging study of Parkinson disease: comparison with conventional diffusion tensor imaging. (2014)
  • Author(s): Kamagata K, Tomiyama H, Hatano T, Motoi Y, Abe O, Shimoji K, Kamiya K, Suzuki M, Hori M, Yoshida M, Hattori N, Aoki S.
  • Journal Title: Neuroradiology Volume: 56 Issue: 3 Pages: 251-258
  • DOI: 10.1007/s00234-014-1327-1
  • Peer Reviewed
• [Journal Article] Analyses of the MAPT, PGRN, and C9orf72 mutations in Japanese patients with FTLD, PSP, andCBS (2013)
  • Author(s): Ogaki K
  • Journal Title: Parkinsonism & Related Disorders Volume: 19 Issue: 1 Pages: 15-20
  • DOI: 10.1016/j.parkreldis.2012.06.019
  • Peer Reviewed
• [Journal Article] Relationship between cognitive impairment and white-matter alteration in Parkinson’s disease with dementia: tract-based spatial statistics and tract-specific analysis. (2013)
  • Author(s): Kamagata K
  • Journal Title: Eur Radiol. Volume: 23(7) Issue: 7 Pages: 1946-1955
  • DOI: 10.1007/s00330-013-2775-4
  • Peer Reviewed
• [Journal Article] Lack of Genetic Associations of PPAR-γ and PGC-1α with Alzheimer’s Disease and Parkinson’s Disease with Dementia. (2013)
  • Author(s): Shibata N, Motoi Y, Tomiyama H, Ohnuma T, Kuerban B, Tomson K, Komatsu M, Shimazaki H, Hattori N, Arai H.
  • Journal Title: Dement Geriatr Cogn Disord Extra Volume: 3 Issue: 1 Pages: 161-7
  • DOI: 10.1159/000351419
  • Peer Reviewed
• [Journal Article] Population-specific frequencies for LRRK2 susceptibility variants in the genetic epidemiology of Parkinson's disease (GEO-PD) consortium. (2013)
  • Author(s): Heckman MG, Soto-Ortolaza AI, Aasly JO, Abahuni N, Annesi G, Bacon JA, Bardien S, Bozi M, Brice A, Brighina L, Carr J, Chartier-Harlin MC, Dardiotis E, Dickson DW, Diehl NN, Elbaz A, Ferrarese C, Fiske B, Gibson JM, Gibson R, Hadjigeorgiou GM, Hattori N, ... , Tomiyama H, et al.
  • Journal Title: Mov Disord Volume: 28 Issue: 12 Pages: 1740-4
  • DOI: 10.1002/mds.25600
  • Peer Reviewed
• [Journal Article] Diffusional kurtosis imaging of cingulate fibers in Parkinson disease: comparison with conventional diffusion tensor imaging. (2013)
  • Author(s): Kamagata K
  • Journal Title: Magn Reson Imaging. Volume: 31(9) Issue: 9 Pages: 1501-1506
  • DOI: 10.1016/j.mri.2013.06.009
  • Peer Reviewed
• [Journal Article] Intronic C9orf72 mutation expanding on neurodegenerative disorders and other diseases (Editorial). (2013)
  • Author(s): Tomiyama H.
  • Journal Title: J Neurol Disord Stroke Volume: 1 Pages: 1009-1009
• [Journal Article] The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants. (2013)
  • Author(s): Heckman MG, Elbaz A, Soto-Ortolaza AI, Serie DJ, Aasly JO, Annesi G, Auburger G, Bacon JA, Boczarska-Jedynak M, Bozi M, Brighina L, Chartier-Harlin MC, Dardiotis E, Destée A, Ferrarese C, Ferraris A, Fiske B, Gispert S, Hadjigeorgiou GM, Hattori N, Ioannidis JP, Jasinska-Myga B, ... , Tomiyama H, et al.
  • Journal Title: Neurobiol Aging Volume: S0197-4580 Pages: 318-7
  • Peer Reviewed
• [Journal Article] 運動ニューロン疾患の遺伝学：update 『わが国のALSにおけるC9ORF72』 (2013)
  • Author(s): 富山弘幸．
  • Journal Title: 臨床神経学 . Volume: 53 Pages: 1074-6
• [Presentation] The first case report describing the moment of sudden respiratory arrest in a patient with Perry syndrome.
  • Author(s): Ryoichi Kurisaki, Hiroyuki Tomiyama, Tetsuro Sakamoto, Kazutoshi Uekawa, Yoshio Tsuboi.
  • Organizer: MDPD international congress 2013
  • Place of Presentation: Seoul, Korea
• [Presentation] Progress in clinical genetics for patients with Parkinson's disease and related disorders - focusing on non-motor aspects.
  • Author(s): H. Tomiyama, N. Hattori.
  • Organizer: MDPD international congress 2013
  • Place of Presentation: Seoul, Korea.
  • Invited
• [Presentation] ALS/FTDにおけるC9orf72遺伝子診断について
  • Author(s): 富山弘幸，大垣光太郎，熱田直樹，李元哲，舩山学，渡辺はづき，中村亮一，吉野英夫，谷藤誠司，田村麻子，内藤寛，谷口彰，藤田浩司，和泉唯信，梶龍兒，服部信孝，祖父江元，Japanese Consortium for Amyotrophic Lateral Sclerosis research (JaCALS)．
  • Organizer: 第58回日本人類遺伝学会大会
  • Place of Presentation: 仙台
• [Presentation] 運動ニューロン疾患の遺伝学：Update わが国のALSにおけるC9ORF72．
  • Author(s): 富山弘幸．
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京
  • Invited
• [Presentation] パーキンソン病．
  • Author(s): 富山弘幸．
  • Organizer: 静清リハビリテーション病院セミナーシリーズ2013
  • Place of Presentation: 静岡
  • Invited
• [Presentation] 新たに見つかった遺伝性パーキンソン病の臨床像．
  • Author(s): 富山弘幸．
  • Organizer: 第７回パーキンソン病・運動障害疾患コングレス（MDSJ）オープニングセミナー
  • Place of Presentation: 東京
  • Invited
• [Presentation] 順天堂大学脳神経内科におけるパーキンソン病の遺伝子解析・遺伝子診断．
  • Author(s): 富山弘幸．
  • Organizer: パーキンソン病学術講演会
  • Place of Presentation: 滋賀草津
  • Invited
• [Book] 12番染色体に連鎖する遺伝性パーキンソン病（PARK8）．日本臨牀「神経症候群 II」． (2014)
  • Author(s): 富山弘幸，服部信孝．
  • Total Pages: 4
  • Publisher: 日本臨牀社
• [Book] 「神経症候群 II」．12番染色体に連鎖する遺伝性パーキンソン病（PARK8）． (2014)
  • Author(s): 富山弘幸，服部信孝．
  • Publisher: 日本臨床