次世代シーケンサーを用いた新規パーキンソン病原因遺伝子の単離

2016 Fiscal Year Research-status Report

• Project/Area Number: 16K09678
• Research Institution: Juntendo University
• Principal Investigator: 西岡 健弥 順天堂大学, 医学部, 准教授 (40348933)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 遺伝子 / パーキンソン病 / 次世代シーケンサー

Outline of Annual Research Achievements

次世代シーケンサーをすでに施行した１家系について解析を行っている．同一家系内に発症者が４名おり，3名についてDNAを回収することができた．既知の遺伝子，SNCA, LRRK2, PINK1, DJ1は存在しないことをSanger sequencingで証明した．次世代シーサーの解析後，CLC　Genomics worbnechを用いて，11万程度のSNPSやindelを同定し，この中から，nonsynonymous exonic variants, frequency<0.01, heterozygous variantsの条件で絞り込みをかけたところ，46遺伝子まで候補原因遺伝子変異を絞り込んだ．次に，これら46遺伝子に対して，primerを作成しSanger sequencingを施行した．これにより46変異が実在することを証明した．現在この46遺伝子について，pubmed上，既報の論文の解析，The human protein atlas, GTEx datasetを用いて，脳内に高発現しているもの，神経疾患と関連のあるもの，またまったく既報の報告がないものに振り分け，16遺伝子まで候補遺伝子を絞り込んでいる．今後これらについて，ion PGMを用いたhigh-throughput解析を行い，さらなる新規原因遺伝子の同定を行っていく．進捗状況は概ね良好である．

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

上記の内容で研究を進めている．現在のところとくに大きく躓くことなく，順調に推移している．

Strategy for Future Research Activity

原因遺伝子を同定した後は，細胞培養実験や動物モデルにて解析を行い，病的なものかどうかの確認，細胞内での発現動向，コードする蛋白質の機能解析を行っていく．

Research Products

• [Int'l Joint Research] University of British Columbia(Canada)
  • Country Name: Canada
  • Counterpart Institution: University of British Columbia
• [Int'l Joint Research] Luxemburg University(ルクセンブルク)
  • Country Name: LUXEMBOURG
  • Counterpart Institution: Luxemburg University
• [Int'l Joint Research] ICM Hospital Pitie Salpetriere(France)
  • Country Name: France
  • Counterpart Institution: ICM Hospital Pitie Salpetriere
• [Journal Article] A novel mutation of CHCHD2 p.R8H in a sporadic case of Parkinson's disease. (2017)
  • Author(s): Ikeda A, Matsushima T, Daida K, Nakajima S, Conedera S, Li Y, Yoshino H, Oyama G, Funayama M, Nishioka K, Hattori N.
  • Journal Title: Parkinsonism and Related Disorders Volume: 34 Pages: 66-68
  • DOI: 10.1016/j.parkreldis.2016.10.018.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] FBXO7 Mutations in Parkinson's Disease and Multiple System Atrophy. (2016)
  • Author(s): Conedera S, Apaydin H, Li Y, Yoshino H, Ikeda A, Matsushima T, Funayama M, Nishioka K, Hattori N.
  • Journal Title: Neurobiology of Aging Volume: 40 Pages: e1-5
  • DOI: 10.1016/j.neurobiolaging.2016.01.003.
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Genetic association between presenilin 2 polymorphisms and Alzheimer’s disease and dementia of Lewy body type in a Japanese population. (2016)
  • Author(s): Suzuki A, Shibata N, Kasanuki K, Nagata T, Shinagawa S, Kobayashi N, Ohnuma T, Takeshita Y, Kawai E, Takayama T, Nishioka K, Motoi Y, Hattori N, Nakayama K, Yamada H, Arai H.
  • Journal Title: Dementia and Geriatric Cognitive Disorders Extra Volume: 16 Pages: 90-97
  • DOI: 10.1159/000444080.
  • Peer Reviewed
• [Journal Article] Schizophrenia as a prodromal symptom in a patient harboring SNCA duplication. (2016)
  • Author(s): Takamura S, Ikeda A, Nishioka K, Furuya H, Tashiro M, Matsushima T, Li Y, Yoshino H, Funayama M, Morinobu S, Hattori N.
  • Journal Title: Parkinsonism and Related Disorders Volume: 25 Pages: 108-109
  • DOI: 10.1016/j.parkreldis.2016.01.028.
  • Peer Reviewed
• [Journal Article] Genetic association between RAGE polymorphisms and Alzheimer's disease and Lewy body dementias in a Japanese cohort: a case-control study. (2016)
  • Author(s): Takeshita Y, Shibata N, Kasanuki K, Nagata T, Shinagawa S, Kobayashi N, Ohnuma T, Suzuki A, Kawai E, Takayama T, Nishioka K, Motoi Y, Hattori N, Nakayama K, Yamada H, Arai H.
  • Journal Title: International Journal of Geriatric Psychiatry Volume: 4 Pages: XX-XX
  • DOI: 10.1002/gps.4600
  • Peer Reviewed
• [Journal Article] Genotype-phenotype correlations of cysteine replacement in CADASIL. (2016)
  • Author(s): Matsushima T, Conedera S, Tanaka R, Li Y, Yoshino H, Funayama M, Ikeda A, Hosaka Y, Okuzumi A, Shimada Y, Yamashiro K, Motoi Y, Nishioka K, Hattori N.
  • Journal Title: Neurobiology of Aging Volume: 2 Pages: e7-e14
  • DOI: 10.1016/j.neurobiolaging.2016.10.026.
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Analysis of GCH1 mutations in the patients with Parkinson’s disease in Japanese population (2016)
  • Author(s): Kenya Nishioka, Hiroyo Yoshino, Takashi Matsushima, Aya Ikeda, Manabu Funayama, Nobutaka Hattori
  • Organizer: 11th Annual Meeting of the Genetic Epidemiology of Parkinson’s disease (GEOPD) Consortium
  • Place of Presentation: Campus Belval, Luxembourg
  • Year and Date: 2016-10-06 – 2016-10-08
  • Int'l Joint Research
• [Presentation] Schizophrenia as a prodromal symptom in a patient harboring SNCA duplication (2016)
  • Author(s): Silvio Conedera, Aya Ikeda, Kenya Nishioka, Shogo Takamura, Takashi Matsushima, Yuanzhe Li, Hiroyo Yoshino, Manabu Funayama, Shigeru Morinobu, Nobutaka Hattori.
  • Organizer: 第57会日本神経学会学術大会
  • Place of Presentation: 神戸コンベンションセンター
  • Year and Date: 2016-05-18 – 2016-05-21
• [Presentation] Analysis of GCH1 mutations in the patients with Parkinson’s disease in Japanese population (2016)
  • Author(s): Hiroyo Yoshino, Kenya Nishioka, Aya Ikeda, Takashi Matsushima, Mitsuaki Oki, Daigo Miyazaki, Yoshiki Sekijima, Ai Hosaka, Takekazu Ohi, Hiroshi Iwanaga, Yuanzhe Li, Manabu Funayama, Nobutaka Hattori.
  • Organizer: 第57会日本神経学会学術大会
  • Place of Presentation: 神戸コンベンションセンター
  • Year and Date: 2016-05-18 – 2016-05-21
• [Book] 家族性パーキンソン病 update annual review 2016 (2016)
  • Author(s): 松島隆史、西岡健弥、服部信孝
  • Total Pages: 9
  • Publisher: 中外医学社
• [Book] 第17番染色体に連鎖するパーキソニズムを伴う前側頭葉型認知症（FTDP-17） (2016)
  • Author(s): 西岡健弥，池田彩，服部信孝
  • Total Pages: 6
  • Publisher: 中外医学社
• [Remarks] 順天堂大学研究者情報データベース１
  • URL: http://www.juntendo.ac.jp/graduate/kenkyudb/search/researcher.php?MID=1762
• [Remarks] 順天堂大学研究者情報データベース２
  • URL: http://www.juntendo.ac.jp/graduate/kenkyudb/search/achievement.php?MID=1762