パーキンソン病および認知機能関連分子とパーソナルゲノム解析

2013 Fiscal Year Annual Research Report

• Project Area: Personal genome-based initiatives toward understanding bran diseases
• Project/Area Number: 22129006
• Research Institution: Kobe University
• Principal Investigator: 戸田 達史 神戸大学, 医学(系)研究科(研究院), 教授 (30262025)
• Co-Investigator(Kenkyū-buntansha): 小林 千浩 神戸大学, 医学(系)研究科(研究院), 准教授 (90324780)
• Project Period (FY): 2010-06-23 – 2015-03-31
• Keywords: パーソナルゲノム / パーキンソン病 / 認知機能 / 多型 / 次世代シークエンサー

Research Abstract

孤発性パーキンソン病遺伝子を同定するため、特にエクソンに存在するRareながら強いパーキンソン病(PD)ゲノム因子を発見するため、とくに孤発性PD患者を中心に、全エクソン塩基配列解読（エクソーム解析）をおこなった。715例のPD患者ゲノムから、全エクソン（エクソーム）を抽出、HiSeq2000シークエンサーで超高速・並列シークエンスをおこなった。BWAソフトウェアでヒト参照配列hg19へマップし、GATKソフトウェアで、参照配列とことなるSNV (single nucleotide variant)を約30万個検出した。715検体のエクソームデータの平均被覆は126。1xであり、全エクソン配列の94。9%のエリアが10x以上で被覆された。これは、孤発性PD患者755人について、全遺伝子の全エクソン塩基配列のほぼすべてが解読できたことを意味する。また優性遺伝性ミオパチーの大家系について、次世代シークエンサーをもちいたエクソーム解析を行い発症者４人にMYH7遺伝子の３塩基欠失変異を同定し、東アジア人で最初のLaing遠位型ミオパチーであることがわかった。

Current Status of Research Progress

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

Reason

おおむね順調に進展している。

Strategy for Future Research Activity

患者データを非患者対照群と比較する全エクソン関連解析をおこない、孤発性パーキンソン病の強いRare variantリスクを発見する。

Research Products

• [Journal Article] Genetic mutations in adipose triglyceride lipase and myocardial up-regulation of peroxisome proliferated activated receptor-γ in patients with triglyceride deposit cardiomyovasculopathy. (2014)
  • Author(s): Hirano K, Tanaka T, Ikeda Y, Yamaguchi S, Zaima N, Kobayashi K, Suzuki A, Sakata Y, Sakata Y, Kobayashi K, Toda T, Fukushima N, Ishibashi-Ueda H, Tavian D, Nagasaka H, Hui SP, Chiba H, Sawa Y, Hori M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 443 Pages: 574-579
  • DOI: 10.1016/j.bbrc.2013.12.003
  • Peer Reviewed
• [Journal Article] The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants. (2014)
  • Author(s): Heckman MG, Elbaz A, Soto-Ortolaza AI, ..., Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium.
  • Journal Title: Neurobiol Aging Volume: 35 Pages: 266.e5-14
  • DOI: doi: 10.1016/j.neurobiolaging.2013.07.013
  • Peer Reviewed
• [Journal Article] A case of Bardet-Biedl syndrome complicated with intracranial hypertension in a Japanese child. (2014)
  • Author(s): Saida K, Inaba Y, Hirano M, Satake W, Toda T, Suzuki Y, Sudo A, Noda S, Hidaka Y, Hirabayashi K, Imai H, Kurokawa T, Koike K.
  • Journal Title: Brain Dev Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1016/j.braindev.2013.10.013
  • Peer Reviewed
• [Journal Article] Modeling Alzheimer's Disease with iPSCs Reveals Stress Phenotypes Associated with Intracellular Aβ and Differential Drug Responsiveness. (2013)
  • Author(s): Kondo T, Asai M, Tsukita K, ..., Kobayashi K, Toda T, ..., Inoue H.
  • Journal Title: Cell Stem Cell Volume: 2 Pages: 487-496
  • DOI: 10.1016/j.stem.2013.01.009
  • Peer Reviewed
• [Journal Article] Myositis with antimitochondrial antibodies diagnosed by musculus rectus abdominis biopsy. (2013)
  • Author(s): Uenaka K, Kowa H, Sekiguchi K, Nagata K, Ohtsuka Y, Kanda F, Toda T.
  • Journal Title: Muscle Nerve Volume: 47 Pages: 766-768
  • DOI: 10.1002/mus.23730
  • Peer Reviewed
• [Journal Article] A novel mutation in the C2 domain of protein kinase C gamma associated with spinocerebellar ataxia type 14. (2013)
  • Author(s): Ueda T, Seki T, Katanazaka K, Sekiguchi K, Kobayashi K, Kanda F, Toda T.
  • Journal Title: J Neurol Volume: 260 Pages: 1664-1666
  • DOI: 10.1007/s00415-013-6916-0
  • Peer Reviewed
• [Journal Article] Inhibition of protein misfolding/aggregation using polyglutamine binding peptide QBP1 as a therapy for the polyglutamine diseases. (2013)
  • Author(s): Popiel HA, Takeuchi T, Burke JR, Strittmatter WJ, Toda T, Wada K, Nagai Y.
  • Journal Title: Neurotherapeutics Volume: 10 Pages: 440-446
  • DOI: 10.1007/s13311-013-0184-7
  • Peer Reviewed
• [Journal Article] Mutations in COQ2 in familial and sporadic multiple-system atrophy. (2013)
  • Author(s): Mitsui J, Matsukawa T, Ishiura H, ..., Satake W, Toda T, ..., Tsuji S.
  • Journal Title: N Engl J Med Volume: 369 Pages: 233-244
  • DOI: 10.1056/NEJMoa1212115
  • Peer Reviewed
• [Journal Article] Impaired viability of muscle precursor cells in muscular dystrophy with glycosylation defects and amelioration of its severe phenotype by limited gene expression. (2013)
  • Author(s): Kanagawa M, Yu CC, Ito C, Fukada SI, Hozoji-Inada M, Chiyo T, Kuga A, Matsuo M, Sato K, Yamaguchi M, Ito T, Ohtsuka Y, Katanosaka Y, Miyagoe-Suzuki Y, Naruse K, Kobayashi K, Okada T, Takeda S, Toda T.
  • Journal Title: Hum Mol Genet Volume: 22 Pages: 3003-3015
  • DOI: 10.1093/hmg/ddt157
  • Peer Reviewed
• [Journal Article] Novel POMGnT1 mutations cause muscle-eye-brain disease in Chinese patients (2013)
  • Author(s): Jiao H, Manya H, Wang S, Zhang Y, Li X, Xiao J, Yang Y, Kobayashi K, Toda T, Endo T, Wu X, Xiong H.
  • Journal Title: Mol Genet Genomics Volume: 288 Pages: 297-308
  • DOI: 10.1007/s00438-013-0749-5
  • Peer Reviewed
• [Journal Article] Molecular pathology of Sandhoff disease with p.Arg505Gln in HEXB: application of simulation analysis. (2013)
  • Author(s): Yasui N, Takaoka Y, Nishio H, Nurputra DK, Sekiguchi K, Hamaguchi H, Kowa H, Maeda E, Sugano A, Miura K, Sakaeda T, Kanda F, Toda T.
  • Journal Title: J Hum Genet Volume: 58 Pages: 611-617
  • DOI: 10.1038/jhg.2013.68
  • Peer Reviewed
• [Journal Article] YY1 binds to α-synuclein 3'-flanking region SNP and stimulates antisense noncoding RNA expression. (2013)
  • Author(s): Mizuta I, Takafuji K, Ando Y, Satake W, Kanagawa M, Kobayashi K, Nagamori S, Shinohara T, Ito C, Yamamoto M, Hattori N, Murata M, Kanai Y, Murayama S, Nakagawa M, Toda T.
  • Journal Title: J Hum Genet Volume: 58 Pages: 711-719
  • DOI: 10.1038/jhg.2013.90
  • Peer Reviewed
• [Journal Article] AGO61-dependent GlcNAc modification primes the formation of functional glycans on α-dystroglycan. (2013)
  • Author(s): Yagi H, Nakagawa N, Saito T, Kiyonari H, Abe T, Toda T, Wu SW, Khoo KH, Oka S, Kato K.
  • Journal Title: Sci Rep Volume: 3 Pages: -
  • DOI: 10.1038/srep03288
  • Peer Reviewed
• [Journal Article] Plasmablasts as migratory IgG-producing cells in the pathogenesis of neuromyelitis optica. (2013)
  • Author(s): Chihara N, Aranami T, Oki S, Matsuoka T, Nakamura M, Kishida H, Yokoyama K, Kuroiwa Y, Hattori N, Okamoto T, Murata M, Toda T, Miyake S, Yamamura T.
  • Journal Title: PLoS One Volume: 8 Pages: -
  • DOI: 10.1371/journal.pone.0083036
  • Peer Reviewed
• [Journal Article] 【遺伝子・再生医療研究から学ぶパーキンソン病】 PARK遺伝子研究の現状 【RAB7L1(PARK16)】 ゲノムワイド関連解析からの知見とさらなる孤発性パーキンソン病遺伝子の発見へ向けて PARK16、BST1、α-synuclein、LRRK2、Tau (2013)
  • Author(s): 佐竹 渉, 戸田 達史
  • Journal Title: 医学のあゆみ Volume: 247 Pages: 1075-1082
• [Journal Article] 【パーキンソン病診療の新しい展開】 パーキンソン病の臨床遺伝学 (2013)
  • Author(s): 戸田 達史
  • Journal Title: Mebio Volume: 30 Pages: 17-22
• [Journal Article] SCA8遺伝子のCTA/CTGリピート数増大をみとめた若年性パーキンソニズムの1例 (2013)
  • Author(s): 宮脇 統子, 関口 兼司, 安井 直子, 上田 健博, 苅田 典生, 戸田 達史
  • Journal Title: 臨床神経学 Volume: 53 Pages: 278-282
  • DOI: 10.5692/clinicalneurol.53.278
  • Peer Reviewed
• [Journal Article] 【神経・精神疾患診療マニュアル】 神経・精神疾患の動向 神経疾患と遺伝子 (2013)
  • Author(s): 佐竹 渉, 戸田 達史
  • Journal Title: 日本医師会雑誌 Volume: 142 Pages: S38-S39
• [Presentation] Genomewide Analysis and Molecular Targeting Therapy for Parkinson’s Disease and Muscular Dystrophy (2014)
  • Author(s): Toda T.
  • Organizer: SYMPOSIUM ON MEMBRANE BIOLOGY
  • Place of Presentation: University of Washington, Seattle, U.S.A.
  • Year and Date: 20140328-20140328
  • Invited
• [Presentation] Exome sequencing of Parkinson's disease in order to identify genetic variants with high disease-risk. (2013)
  • Author(s): Satake W, Suzuki Y, Ando Y, Tomiyama H, Yamamoto M, Murata M, Hattori N, Tsuji S, Sugano S, Toda T.
  • Organizer: American Society of Human Genetics Annual meeting 2013.
  • Place of Presentation: Boston Convention & Exhibition Center (BCEC), Boston, U.S.A.
  • Year and Date: 20131023-20131023
• [Presentation] Search for rare-variant risks of Parkinson’s disease by sequencing of candidate genes and exome sequencing. (2013)
  • Author(s): Satake W, Ando Y, Tomiyama H, Takeda A, Hasegawa K, Yamamoto M, Murata M, Hattori N, Toda T.
  • Organizer: The MDS 17th International Congress of Parkinson's Disease and Movement Disorders.
  • Place of Presentation: Sydney Convention and Exhibition Centre, Sydney, Australia
  • Year and Date: 20130620-20130620
• [Presentation] GWAS and pathology: How are they connected? (2013)
  • Author(s): Toda T.
  • Organizer: The MDS 17th International Congress of Parkinson's Disease and Movement Disorders.
  • Place of Presentation: Sydney Convention and Exhibition
  • Year and Date: 20130617-20130617
  • Invited
• [Remarks] 神経内科 神戸大学大学院医学系研究科・内科学講座
  • URL: http://www.med.kobe-u.ac.jp/sinkei/
• [Remarks] 神戸大学大学院 医学研究科 生理学・細胞生物学講座 分子脳科学分野
  • URL: http://www.med.kobe-u.ac.jp/clgene/