MYBPC3における早発性コドン変異は,無意味な媒介による慢性的な衰退の活性化による高縮性心筋病を引き起こす

Timon Seeger^1,2, Rajani Shrestha^1,2, Chi Keung Lam^1,2

¹Stanford Cardiovascular Institute (T.S., R.S., C.K.L., C.C., W.L.M., E.L., A.W., M.G, J.L., A.O., S.L., H.Y., M.M., M.W., E.A.A., I.K., J.C.W.), Stanford University School of Medicine, CA.

Circulation

|December 28, 2018

まとめ

MYBPC3の変異は,無感覚媒介の衰退を活性化して,心臓細胞の異常なカルシウム処理を引き起こします. この経路を阻害することで患者の細胞の心臓機能が正常化しました

科学分野:

心血管生物学
幹細胞生物学
分子遺伝学

背景:

ハイパルトロフィック心筋病 (HCM) は,MYBPC3の変異によって引き起こされ,早期終結コドン (PTC) に繋がります.
MYBPC3 PTC変異がHCMを誘発する正確なメカニズムは不明である.
この研究では,ヒト誘発性多能幹細胞由来心筋細胞 (iPSC-CMs) を使用して,MYBPC3 PTC変異に関連したHCMの分子病原性を調査しています.

研究の目的:

MYBPC3 PTC変異媒体のHCM病原性の基礎にある分子メカニズムを解明する.
HCMの発達における異常なカルシウム処理と遺伝子発現の役割を調査する.
HCMに対するMYBPC3ハプロイン不全の寄与を決定する.

主な方法:

MYBPC3 PTC変異を有するHCM患者の同位性IPSCラインの生成は,ゲノム編集によるものです.
iPSC-CMの包括的なフェノタイプとトランスクリプトーム解析
無意味媒介性衰退 (NMD) 経路の役割と治療的抑制の調査.

主要な成果:

HCM iPSC-CMは,構造的または収縮的欠陥なしに,長時間的な衰退と高まった腹筋カルシウムとの異常なカルシウム処理を示した.
減少したMYBPC3mRNAですが,比較可能なタンパク質レベルは,有意なMYBPC3ハプロイン不足を示していません.
無意味な腐敗経路の活性化と異常な心臓遺伝子発現が観察され, in vitro HCM シグネチャーを構成しました.
NMDの抑制により,分子フェノタイプが逆転し,カルシウム処理が正常化しました.

結論:

iPSC- CMにおけるMYBPC3 PTC変異は,MYBPC3ハプロイン不全とは無関係に異常なカルシウムシグナル伝達と分子不調を引き起こします.
この研究は,無意味媒介による衰退経路の慢性的な活性化とHCMの発達を直接関連付ける最初の証拠を提供します.
NMD経路をターゲットにすることは,HCMの潜在的な治療戦略を提供します.

キーワード:

心筋細胞ハイパルトロフィック心筋病

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