Aim to detect a novel pathogenic mutation in a familial Parkinson's disease

• Project/Area Number: 16K09678
• 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: Nishioka Kenya 順天堂大学, 医学部, 准教授 (40348933)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: パーキンソン病 / 遺伝子 / 神経変性疾患 / 遺伝子変異 / 次世代シーケンサー

Outline of Final Research Achievements

We aim to detect a novel pathogenic mutation among a family presenting a high concentration of Parkinson's disease (PD). We used whole genome sequencing (HiSeq2500 sequencer) and focus on 46 candidate gene from the family. Following, we established ion Torrent system to screen 46 candidate gene for 50 familial PD. As a result, we detected 10 genes as a further candidate pathogenic gene, which are AHDC1, AP2A2, FBLN2, KIAA0947, NRAP, OLFML2B, TM6SF1, FLG-AS1, HMCN2, MUC19. Next, we will plan to add more samples to confirm the genetic risk factor of the onset of PD.

Academic Significance and Societal Importance of the Research Achievements

パーキンソン病（PD）は、振戦、固縮、歩行困難、動作緩慢といった運動症状を主体とした加齢が重要な危険因子の疾患である。超高齢社会に伴い、その患者数は今後益々増加することが予想される。人口構成の高齢化に伴い、その有病率は増加の一途を辿っている。更なる病態解明と分子レベルにおける新規治療薬の開発そして疾患修飾療法が望まれる。これまで遺伝性PD研究は孤発型PDの病態解明へ重要なヒントを提供しており、病態解明への近道である。今回我々は常染色体優性遺伝形式をとり、既知の遺伝子変異を持たないPD の一家系に注目し、全ゲノムシーケンスを施行し、病的遺伝子の探索を行う．

Research Products

• [Int'l Joint Research] University of British Columbia(Canada)
• [Int'l Joint Research] University of British Columbia(Canada)
• [Int'l Joint Research] Luxemburg University(ルクセンブルク)
• [Int'l Joint Research] ICM Hospital Pitie Salpetriere(France)
• [Journal Article] Tau aggregation and seeding analyses of two novel MAPT variants found in patients with motor neuron disease and progressive parkinsonism. (2019)
  • Author(s): Nakayama S, Shimonaka S, Elahi M, Nishioka K, Oji Y, Matsumoto SE, Li Y, Yoshino H, Mogushi K, Hatano T, Sato T, Ikura T, Ito N, Motoi Y, Hattori N.
  • Journal Title: Neurobiology of Aging Volume: 19 Pages: 240.e13-240.e22
  • DOI: 10.1016/j.neurobiolaging.2019.02.016
  • Peer Reviewed
• [Journal Article] Clinical heterogeneity of frontotemporal dementia and Parkinsonism linked to chromosome 17 caused by MAPT N279K mutation in relation to tau positron emission tomography features (2019)
  • Author(s): Ikeda Aya、Shimada Hitoshi、Nishioka Kenya、Takanashi Masashi、Hayashida Arisa、Li Yuanzhe、Yoshino Hiroyo、Funayama Manabu、Ueno Yuji、Hatano Taku、Sahara Naruhiko、Suhara Tetsuya、Higuchi Makoto、Hattori Nobutaka
  • Journal Title: Movement Disorders Volume: 34 Issue: 4 Pages: 568-574
  • DOI: 10.1002/mds.27623
  • Peer Reviewed / Open Access
• [Journal Article] Isolated nigral degeneration without pathological protein aggregation in autopsied brains with LRRK2 p.R1441H homozygous and heterozygous mutations (2018)
  • Author(s): Takanashi M, Funayama M (Contributed equally), Matsuura E, Yoshino H, Li Y, Tsuyama S, Takashima H, Nishioka K, Hattori N
  • Journal Title: Acta Neuropathologica Communications Volume: 6 Issue: 1 Pages: 105-105
  • DOI: 10.1186/s40478-018-0617-y
  • Peer Reviewed / Open Access
• [Journal Article] GCH1 mutations in dopa-responsive dystonia and Parkinson's disease. (2018)
  • Author(s): Yoshino H, Nishioka K, Li Y, Oji Y, Oyama G, Hatano T, Machida Y, Shimo Y, Hayashida A, Ikeda A, Mogushi K, Shibagaki Y, Hosaka A, Iwanaga H, Fujitake J, Ohi T, Miyazaki D, Sekijima Y, Oki M, Kusaka H, Fujimoto KI Ugawa Y, Funayama M, Hattori N.
  • Journal Title: Journal of Neurology Volume: 265(8) Issue: 8 Pages: 1860-1870
  • DOI: 10.1007/s00415-018-8930-8
  • Peer Reviewed / Open Access
• [Journal Article] COQ2 variants in Parkinson's disease and multiple system atrophy. (2018)
  • Author(s): Mikasa M, Kanai K, Li Y, Yoshino H, Mogushi K, Hayashida A, Ikeda A, Kawajiri S, Okuma Y, Kashihara K, Sato T, Kondo H, Funayama M, Nishioka K, Hattori N.
  • Journal Title: J Neural Transm (Vienna) Volume: - Issue: 6 Pages: 938-944
  • DOI: 10.1007/s00702-018-1885-1
  • Peer Reviewed / Open Access
• [Journal Article] Genetic analysis of TMEM230 in Japanese patients with familial Parkinson’s disease. (2018)
  • Author(s): Conedera SA, Li Y, Funayama M, Yoshino H, Nishioka K, Hattori N.
  • Journal Title: Parkinsonism Relat Disord Volume: 48 Pages: 107-108
  • DOI: 10.1016/j.parkreldis.2017.12.020
  • Peer Reviewed
• [Journal Article] Association between abnormal nocturnal blood pressure profile and dementia in Parkinson's disease. (2018)
  • Author(s): Tanaka R, Shimo Y, Yamashiro K, Ogawa T, Nishioka K, Oyama G, Umemura A, Hattori N.
  • Journal Title: Parkinsonism and Related Disorders Volume: 46 Pages: 24-29
  • DOI: 10.1016/j.parkreldis.2017.10.014
  • Peer Reviewed
• [Journal Article] Marked reduction in striatal dopamine transporter uptake during the early stage of motor symptoms in patients with the MAPT N279K mutation (2018)
  • Author(s): Takeshige H, Nakayama S, Nishioka K, Li Y, Motoi Y, Hattori N.
  • Journal Title: Internal Medicine Volume: in press
  • Peer Reviewed
• [Journal Article] DNAJC12 and dopa-responsive nonprogressive parkinsonism. (2017)
  • Author(s): Straniero L, Guella I, Cilia R, Parkkinen L, Rimoldi V, Young A, Asselta R, Sold, G, Sossi V, Stoessl AJ, Priori A, Nishioka K, Hattori N, Follett J, Rajput A, Blau N, Pezzoli G, Farrer MJ, Goldwurm S, Rajput AH, Duga S.
  • Journal Title: Annals of Neurology Volume: 82 Issue: 4 Pages: 640-646
  • DOI: 10.1002/ana.25048
  • Peer Reviewed
• [Journal Article] Homozygous alpha-synuclein p.A53V in familial Parkinson's disease. (2017)
  • Author(s): Yoshino H, Hirano M, Stoessl AJ, Imamichi Y, Ikeda A, Li Y, Funayama M, Yamada I, Nakamura Y, Sossi V, Farrer MJ, Nishioka K, Hattori N.
  • Journal Title: Neurobiology of Aging Volume: 57 Pages: 248.e7-248.e12
  • DOI: 10.1016/j.neurobiolaging.2017.05.022
  • Peer Reviewed / Open Access
• [Journal Article] A novel mutation of CHCHD2 p.R8H in a sporadic case of Parkinson's disease (2017)
  • Author(s): Ikeda, Aya; Matsushima, Takashi; Daida, Kensuke; Nakajima, Sho; Conedera, Silvio; Li, Yuanzhe; Yoshino, Hiroyo; Oyama, Genko; Funayama, Manabu; Nishioka, Kenya; Hattori, Nobutaka
  • Journal Title: PARKINSONISM & RELATED DISORDERS Volume: 34 Pages: 66-68
  • DOI: 10.1016/j.parkreldis.2016.10.018
  • Peer Reviewed
• [Journal Article] <i>CSF1R</i> Mutation p.G589R and the Distribution Pattern of Brain Calcification (2017)
  • Author(s): Daida K, Nishioka K, Li Y, Nakajima S, Tanaka R, Hattori N.
  • Journal Title: Internal Medicine Volume: 56 Issue: 18 Pages: 2507-2512
  • DOI: 10.2169/internalmedicine.8462-16
  • NAID: 130006078597
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Genotype-phenotype correlations of cysteine replacement in CADASIL (2017)
  • Author(s): Matsushima, Takashi; Conedera, Silvio; Tanaka, Ryota; Li, Yuanzhe; Yoshino, Hiroyo; Funayama, Manabu; Ikeda, Aya; Hosaka, Yuka; Okuzumi, Ayame; Shimada, Yoshiaki; Yamashiro, Kazuo; Motoi, Yumiko; Nishioka, Kenya; Hattori, Nobutaka
  • Journal Title: NEUROBIOLOGY OF AGING Volume: 50 Pages: 169.e7-169.e14
  • DOI: 10.1016/j.neurobiolaging.2016.10.026
  • Peer Reviewed
• [Journal Article] FBXO7 mutations in Parkinson's disease and multiple system atrophy. (2016)
  • Author(s): Conedera S, Apaydin H, Li Y, et al.
  • Journal Title: Neurobiol Aging. Volume: 40 Pages: 192.e1-192.e5
  • 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, et al.
  • Journal Title: Dement Geriatr Cogn Dis Extra. Volume: 16 Issue: 1 Pages: 90-97
  • DOI: 10.1159/000444080
  • Peer Reviewed
• [Journal Article] Schizophrenia as a prodromal symptom in a&nbsp;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 Relat Disord. Volume: S1353-8020 Pages: 30028-1
  • DOI: 10.1016/j.parkreldis.2016.01.028
  • Peer Reviewed / Open Access
• [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 Issue: 12 Pages: 1241-1246
  • DOI: 10.1002/gps.4600
  • Peer Reviewed
• [Presentation] Brain pathology, functional analysis and fly models of CHCHD2 p.T61I (2018)
  • Author(s): Kenya Nishioka1, Aya Ikeda, Hongrui Meng, Masashi Takanashi, Hiroyo Yoshino, Yuanzhe Li, Yuzuru Imai, Manabu Funayama, Nobutaka Hattori
  • Organizer: Genetic Epidemiology of Parkinson's Disease, Paris, 2018
  • Int'l Joint Research
• [Presentation] Comprehensive study of LRRK2 mutations in familial Parkinson's disease in Japan (2018)
  • Author(s): Kenya Nishioka, Aya Ikeda, Hiroyo Yoshino, Yuanzhe Li, Manabu Funayama, Nobutaka Hattori
  • Organizer: 日本人類遺伝学会 第63回大会
  • Int'l Joint Research
• [Presentation] Digenic mutations of parkin-PINK1, PINK1-LRRK2, and LRRK2-PINK1 in familial Parkinson’s disease (2018)
  • Author(s): Kenya Nishioka, Yuanzhe Li, Hiroyo Yoshino, Arisa Hayashida, Aya Ikeda, Kotaro Ogaki, Manabu Funayama, Nobutaka Hattori
  • Organizer: 第50回日本神経学会学術大会
  • Int'l Joint Research
• [Presentation] HOMOZYGOUS ALPHA-SYNUCLEIN A53V IN FAMILIAL PARKINSON'S DISEASE (2017)
  • Author(s): Kenya Nishioka, Makito Hirano, A. Jon Stoessl, Hiroyo Yoshino, Yoko Imamichi, Aya Ikeda, Yuanzhe Li, Manabu Funayama, Ikuko Yamada, Yusaku Nakamura, Vesna Sossi, Matthew J. Farrer, Nobutaka Hattori.
  • Organizer: The XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] The correlation of CHCHD2 mutations and alpha-synculein in the brain pathology and fly models (2017)
  • Author(s): Kenya Nishioka, Aya Ikeda, Masashi Takanashi, Hiroyo Yoshino, Yuanzhe Li, Manabu Funayama, Yuzuru Imai, Nobutaka Hattori.
  • Organizer: Genetic Epidemiology of Parkinson’s disease
  • Int'l Joint Research
• [Presentation] Missense mutations and multiplications of alpha-synuclein in familial Parkinson’s disease; genotype-phenotype correlation (2017)
  • Author(s): Kenya Nishioka, Hiroyo Yoshino, Yuanzhe Li, Manabu Funayama, Tara Candido, A. Jon Stoessl, Matthew J Farrer, Nobutaka Hattori.
  • Organizer: The American Society of Human Genetics
  • Int'l Joint Research
• [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
  • 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
• [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
• [Book] II. 病因 1. 関連遺伝子 (11) VPS13C パーキンソン病（第２版） 基礎・臨床研究のアップデート (2018)
  • Author(s): 林田有紗、西岡 健弥、服部信孝
  • Total Pages: 5
  • Publisher: 日本臨床社
• [Book] Parkinson病のゲノム医療 (2017)
  • Author(s): 西岡健弥 李元哲 吉野浩代 服部信孝
  • Publisher: 科学評論社
• [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 研究者情報ベース
  • URL: https://www.juntendo.ac.jp/graduate/kenkyudb/maintenance.html?MID=1762
• [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