JP2016086787A - パーキンソン病の診断 - Google Patents
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Abstract
【解決手段】常染色体優性遺伝性パーキンソン病を診断する目的で、生体試料のCHCHD2中の突然変異を検出する方法。
【選択図】なし
Description
従って、本発明の課題は、新たな遺伝性パーキンソン病の診断手段を提供することにある。
〔2〕CHCHD2中の突然変異が、c.182C>T(p.Thr 61 Ile)、c.434G>A(p.Arg 145 Gln)又はc.300+5G>Aである〔1〕記載の検出方法。
〔3〕CHCHD2中の突然変異検出用試薬を含有する常染色体優性遺伝性パーキンソン病診断薬。
〔4〕CHCHD2中の突然変異が、CHCHD2中のc.182C>T(p.Thr 61 Ile)c.434G>A(p.Arg 145 Gln)又はc.300+5G>Aである〔3〕記載の診断薬。
前記突然変異ポリペプチドの検出には、前記変異箇所を特異的に認識する抗体が用いられる。
A.方法
(1)被験者及び突然変異スクリーニング
本研究は、順天堂大学医学部の倫理委員会によって承認された。患者及び対照被験者を含む本研究における全ての参加者は日本人であり、順天堂大学DNAバンクから選択された。全員にインフォームドコンセントを行った。患者は全て、神経内科専門医によって英国PD Society Brain Bank臨床診断基準に従いPDと診断された。全ての対照被験者は、神経内科専門医によって神経疾患ではないことが確認された。我々は、少なくとも連続する二世代の内に罹患した家族を有するADPD患者を選択した。
形質移入の前に、5日間(SK−N−SH細胞及びSH−SY5Y細胞)又は24時間(HeLa細胞)に亘り組織培養プレートに細胞を播種した。Lipofectamine 2000試薬(Life Technologies)を用い、製造業者の推奨に従って培養細胞に形質移入を行った。
野生型(wt)及び突然変異ゲノムCHCHD2 DNAフラグメント(c.182C>T、c.300+5G>A、及びc.434G>A)を、pCR−Blunt II−TOPOベクター(Life Technologies)にクローニングし、その後pcDNA3.1/myc−His−A(Life Technologies)中のKpnI−XhoIサイトに移行させ、pcDNA3.1−CHCHD2(wt、c.182C>T、c.300+5G>A、及びc.434G>A)を作製した。隣接するイントロン配列(上流に52ヌクレオチド(nts)及び下流に14nts)を有するCHCHD2エクソン2(wt及びc.300+5G>A)をpSPL3にサブクローニングしてpSPL3−CHCHD2(wt及びc.300+5G>A)を作製した。TRI試薬(Life Technologies)に続いてRQ1 DNase(Promega、米国ウィスコンシン州マディソン)処理を用い、形質移入から24時間後に総RNAを抽出した。Superscript II逆転写酵素(Life Technologies)又はReverTra Ace(東洋紡株式会社、日本、大阪)を用いてランダムプライマーによりcDNAを合成した。形質移入されたpcDNAスプライシングミニ遺伝子の突然変異誘発性エクソンスキッピングを検出するための増幅に2つのプライマー対を使用した。製造業者の指示書に従い、PCR増幅フラグメントと共にRiboprobe in vitro転写システム(Promega)を用いてCHCHD2エクソン2の5’スプライス部位中に[α−32P]−UTP標識化RNAを合成した。Ohe他(Mol Cell Biol. 2010; 30: 2220-2228)の記載のようにRNA電気泳動移動度シフト解析を行った。精製されたU1 snRNPは、Reinhard Luhrmann博士(Max Planck Institute)から寄贈された。
本研究で使用した抗体は、抗CHCHD2抗体(19424-1-AP、Proteintech、米国イリノイ州シカゴ)、抗α−チューブリン抗体(T9026、Sigma-Aldrich、米国ミズーリ州セントルイス)、抗アセチルヒストンH3抗体(06-599、Merck Millipore、米国マサチューセッツ州ビレリカ)、抗Complex I NDUFA9抗体(MS111、MitoSciences、米国オレゴン州ユージーン)、抗Tom20抗体(sc-11415、Santa Cruz Biotechnology、米国テキサス州ダラス)、抗OPA1抗体(612606、BD Biosciences、米国ニュージャージー州フランクリンレイクス)、抗Hsp60抗体(SMC-110、StressMarq Biosciences、カナダ、バンクーバー州ビクトリア)、及び抗FLAG抗体(F1804、Sigma-Aldrich)を含む。
Amo他(Biochem. J. 2007; 404: 345-351)に記載されるようにSK−N−SH神経芽腫細胞からのミトコンドリアの単離を行った。SK−N−SH細胞由来のミトコンドリアに富む画分を、氷上にて30分間、1%Triton X−100を含む、又は含まないトリプシン(0、0.1、0.3、1、3、10、30、及び100μg)を用いて消化した。今井譲博士(順天堂大学)から提供されたヒト胎児脳cDNAライブラリーからCHCHD2コーディング領域を増幅した。cDNAフラグメントをpcDNA3.1−C−3xFLAGへとクローニングした。Quikchange Lightning site-directed mutagenesis kit(Stratagene、米国カリフォルニア州ラホーヤ)を用いて部位特異的変異誘発を行い、CHCHD2点突然変異(c.182C>T、c.300+5G>A、及びc.434G>A)を作出した。PCRにより欠失突然変異体(ΔMTS)を作出した。免疫蛍光顕微鏡法及び免疫電子顕微鏡法にはHeLa細胞を使用した。共焦点顕微鏡法により外因性CHCHD2の局在を検出した。Hoechst 33258(Life Technologies)を用いて核を対比染色した。二次抗体として抗マウスイムノゴールド抗体(EM.GMTA10、BBI Solutions、英国カーディフ)を用いて、Ishikawa他(PLoS One 2014; 9: e94645)に記載されるように免疫電子顕微鏡解析を行った。
SNPHitLinkを用い、ハーディー−ワインベルク平衡P値>0.05、対照における最小コールレート1、最大信頼>0.02、最小区間100kb、及び最小マイナーアレル頻度(MAF)0.2を有するSNPを選択した。Merlinソフトウェア、及び疾患頻度0.001を用いてパラメトリックマルチポイント連鎖解析を行った。罹患していない患者の兄弟姉妹及び子供達の表現型を0と表した(表現型なし)。517名の孤発性PD患者と559名の非罹患対照被験者との間でアレル頻度の有意性を算出するため多重検定に対するボンフェローニ補正によるカイ二乗検定を使用した。JMP 8(SAS Institute、米国ノースカロライナ州ドライブケーリー)を用いて、本研究で見出された変異型のオッズ比(OR)及び95%信頼区間(CI)を算出した。全ての統計学的解析において、P値<0.05を統計学的に有意とした。
次世代シーケンシングを用いて、我々は、4つの症例において累計230万を超える変異型を検出した。同定された変異型を以下の基準に従って選別した:(1)ポジティブ異質性ロッド値(HLOD)>1を有する領域に位置する;(2)dbSNP132を含まない;(3)エクソン部位又はスプライス部位に位置する;(4)異型接合状態で保有される;(5)非同義であるか、又は異常スプライシングを引き起こすと予想される;(6)サンガーシーケンシングによって確認される;及び(7)500名を超える非罹患日本人対照(1000対立遺伝子)には見出されない。1つの変異型のみがこれらの選別基準を満たした(表1)。
CHCHD2は、ミトコンドリア呼吸において重要な役割を果たし、ミトコンドリア内膜腔に局在し、シトクロムcオキシダーゼ活性に関与する。よって、CHCHD2遺伝子はミトコンドリア呼吸と強く結びついたパーキンソン病の第1原因遺伝子である。
Claims (4)
- 常染色体優性遺伝性パーキンソン病を診断する目的で、生体試料のCHCHD2中の突然変異を検出する方法。
- CHCHD2中の突然変異が、c.182C>T(p.Thr 61 Ile)、c.434G>A(p.Arg 145 Gln)又はc.300+5G>Aである請求項1記載の検出方法。
- CHCHD2中の突然変異検出用試薬を含有する常染色体優性遺伝性パーキンソン病診断薬。
- CHCHD2中の突然変異が、CHCHD2中のc.182C>T(p.Thr61 Ile)c.434G>A(p.Arg 145 Gln)又はc.300+5G>Aである請求項3記載の診断薬。
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CN108841949A (zh) * | 2018-07-10 | 2018-11-20 | 北京大学 | 帕金森病早期检测和诊断试剂盒及装置 |
-
2014
- 2014-11-11 JP JP2014228827A patent/JP6468586B2/ja active Active
Non-Patent Citations (3)
Title |
---|
HATANO T. ET AL.: "Pathogenesis of familial Parkinson's disease: new insights based on monogenic forms of Parkinson's", J. NEUROCHEM., vol. Vol. 111, JPN6018036311, 2009, pages pp. 1075-1093 * |
SATAKE W. ET AL.: "Genome-wide association study identifies common variants at four loci as genetic risk factors for P", NAT. GENET., vol. Vol. 41, JPN6018036309, 2009, pages pp. 1303-1307 * |
深江治郎 ほか: "家族性パーキンソン病の分子遺伝学", BIO CLINICA, vol. Vol. 26, JPN6018036310, 2011, pages pp. 696-700 * |
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CN108841949A (zh) * | 2018-07-10 | 2018-11-20 | 北京大学 | 帕金森病早期检测和诊断试剂盒及装置 |
CN108841949B (zh) * | 2018-07-10 | 2021-03-02 | 北京大学 | 帕金森病早期检测和诊断试剂盒及装置 |
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