GATA6は大動脈弁の改造を調節し,そのハプロイン不足は右-左型の二動脈弁につながる
Lara Gharibeh1, Hiba Komati1, Yohan Bossé2
1Department of Biochemistry, Microbiology, and Immunology, Molecular Genetics and Cardiac Regeneration Laboratory, University of Ottawa, Ontario, Canada (L.G., H.K., R.H., M.T., M.N.).
Circulation
|March 24, 2018
まとめ
GATA6の遺伝的変異は,最も一般的な先天性心不全である双動脈弁 (BAV) と関連しています. 心筋細胞のGATA6欠乏は,弁の発達を妨害し,BAVに対する新しい治療目標を提供します.
科学分野:
- 心血管遺伝学
- 発達生物学
- 生まれつき の 心臓 障害
背景:
- バイコスピッド大動脈弁 (BAV) は最も一般的な先天性心不全であり,人口の1~2%に罹患する.
- BAVは早発性大動脈弁疾患の重要な危険因子であり,多くの場合,弁の置換を必要とします.
- BAVの遺伝的基盤と病原性メカニズムはほとんど不明である.
研究 の 目的:
- 二動脈弁 (BAV) の遺伝的基礎と分子メカニズムを調査する.
- BAV の発現における GATA6 遺伝子の役割を特定する.
- BAVの病原性を研究するための適切な動物モデルを確立する.
主な方法:
- ゲータ6の異卵性マウスの心臓の構造と機能を評価した.
- BAV症例と対照群におけるヒトGATA6遺伝子変異を分析した.
- マウスとヒトの組織におけるGATA6の表現を定量化した.
- 培養細胞でメカニズム研究を行った.
主要な成果:
- ヒトの状態を反映した右左 (RL) 型のBAVの発生率が高い.
- ヒトのBAVサンプルでは正常な三弁と比較して低いGATA6トランスクリプトレベルが観察されました.
- Gata6ハプロイン欠乏症は,マトリックスメタルプロテインアース9のようなシグナル分子を乱すことで,弁の再構築と細胞外マトリックス組成を損なう.
- GATA6の喪失は二次心場ミオサイトで起こりますが,内皮細胞やニューラル・クライスト細胞は BAVのフェノタイプを複製していません.
結論:
- BAVの発達に寄与する新しい細胞および分子メカニズムを特定した.
- 人間のBAVの最も一般的な形態のマウスモデルを確立しました.
- この発見は,BAVの病原性を理解し,新しい治療法を開発するための道を開きます.
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