基于iPSC的可变临床表现模型,用于过敏心肌病的变异性临床表现
Rubén Escribá1,2,3, José M Larrañaga-Moreira4,5, Yvonne Richaud-Patin1,2,3
1Regenerative Medicine Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain (R.E., Y.R.-P., L.P., I.L., S.J.-D., A.M.-G., A.R.).
Circulation research
|June 15, 2023
概括
遗传修饰剂影响过度缩性心肌病 (HCM) 的严重程度. 一种MYH7变异与MYBPC3变异相结合,解释了患有遗传性心脏病的兄弟姐妹的不同临床结果.
科学领域:
- 心血管遗传学 心血管遗传学
- 干细胞生物学 干细胞生物学
- 分子心脏病学分子心脏病学
背景情况:
- 增高性心肌病变 (HCM) 是一种常见的遗传性心脏病,通常导致心力衰竭和心脏突然死亡.
- 遗传因素是HCM的关键,但多个基因变异和修饰剂对疾病呈现的影响仍然不清楚.
- 研究基因型-表型相关性对于理解HCM复杂遗传至关重要.
研究的目的:
- 探索患有HCM和不同临床表现的兄弟姐妹的基因型-表型关系.
- 阐明基因修饰剂在HCM表达性中的作用.
- 用患者特异性诱导多能干细胞衍生心肌细胞 (iPSC-CMs) 进行功能遗传研究.
主要方法:
- 使用CRISPR/Cas9基因组编辑生成了针对患者的iPSC-CM和同源对照.
- 在iPSC-CM中评估了线粒体生物能学和激发-收缩合.
- 进行全外体序列测序以识别潜在的基因修饰者.
- 在iPSC-CM中功能性评估候选变体.
主要成果:
- 突变的iPSC-CMs表现出线粒体功能受损和激发-收缩合的改变.
- 一种致病性MYBPC3变种是必要的,但不足以使iPSC-CM过度兴奋.
- 在严重受影响的兄弟姐妹中,全外因子测序确定了MYH7 (p.Ile1927Phe) 中一个未知意义的变异.
- 功能评估证实了MYH7变种作为修饰者的作用.
结论:
- MYH7 p.Ile1927Phe变种作为HCM的修饰剂,在与MYBPC3截断变种同时发生时影响疾病表达性.
- 基于iPSC的临床不一致个体的建模是评估基因修饰剂效应的强大工具.
- 这项研究增强了对高性心肌病的遗传决定因素的理解.
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