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

2018 Fiscal Year Annual Research 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: パーキンソン病 / 遺伝子変異 / 次世代シーケンサー

Outline of Annual Research Achievements

家族集積が濃厚な既知の病的遺伝子変異を持たない常染色体優性遺伝形式の一家系に注目した。患者3名は典型的なパーキンソン症状を呈していた。この家系の3名のDNAへ、アジレント社SureSelectXT HumanAllExon V5+UTRs Kitを用いてエクソン領域を濃縮し、イルミナ社HiSeq2500シーケンサーで100 bp pair endシーケンスを実施した。すべてのvariantを拾い上げ、Burrows-Wheeler AlignerとGRCh37 human reference genomeを使用して、シーケンス配列をアライメントし、GATK (version 4.0.1.1)とANNOVARを使用してvariantのアノテーションを行った。病的変異の抽出法として、non-synonymous variant→頻度0.1%以下→heterozygous variant→患者3名で共通のvariantを絞り込み、46の候補遺伝子を同定した。次に他の家族性PD群内の頻度を見るため、候補遺伝子全てのエクソン領域をカバーするプライマーを設計し、IonPGMを用いて50名の家族性PDについて変異スクリーニングを行った。結果、50名中17名の患者から10の病的遺伝子候補に相当するrare variantを同定した（AHDC1, AP2A2, FBLN2, KIAA0947, NRAP, OLFML2B, TM6SF1, FLG-AS1, HMCN2, MUC19）。さらにサンガー法にて実際に遺伝子変異の有無を確認したところ、AHDC1, AP2A2, KIAA0497、HMCN2に変異の存在を確認した。In silico解析にてアミノ酸変換にてFLG-AS1, HMCN2, MUC19の3つへ絞り込みをかけた。今後はこの３つの遺伝子に対して、頻度解析を行う。

Research Products

• [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: S0197-4580
  • 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 A, Shimada H, Nishioka K, Takanashi M, Hayashida A, Li Y, Yoshino H, Funayama M, Ueno Y, Hatano T, Sahara N, Suhara T, Higuchi M, Hattori N.
  • Journal Title: Movement Disorders Volume: 34 Pages: 568-574
  • DOI: 10.1002/mds.27623.
  • Peer Reviewed
• [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, Matsuura E, Yoshino H, Li Y, Tsuyama S, Takashima H, Nishioka K, Hattori N.
  • Journal Title: Acta Neuropathological Communications Volume: 6 Pages: 105-114
  • DOI: 10.1186/s40478-018-0617-y.
  • Peer Reviewed
• [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: 256 Pages: 1860-1870
  • DOI: 10.1007/s00415-018-8930-8.
  • Peer Reviewed
• [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: Journal of Neural Transmission Volume: 125 Pages: 937-958
  • DOI: 10.1007/s00702-018-1885-1
  • Peer Reviewed
• [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 and related disorders Volume: 48 Pages: 107-108
  • DOI: 10.1016/j.parkreldis.2017.12.020.
  • 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
• [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