来自患者的诱导多能干细胞用于研究与高伤心肌病相关的非正规拼接变体

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Joanna Jager¹, Marta Ribeiro², Marta Furtado³

¹University College London Institute of Cardiovascular Science, Rayne Institute, 5 University Street, London WC1E 6JF, United Kingdom.

Stem cell research

|October 24, 2024

概括

在MYBPC3的内基区域的遗传变异通过影响mRNA拼接,导致高性心肌病 (HCM). 诱导的多能干细胞衍生的心肌细胞显示出对这些拼接缺陷的差异性反应,有助于疾病研究.

科学领域:

心血管遗传学心血管遗传学
分子心脏病学分子心脏病学
干细胞生物学干细胞生物学

背景情况:

超性心肌病变 (HCM) 是一种主要的遗传性心肌疾病,是心脏突然死亡的重要原因.
目前对HCM的遗传测试往往错过了内基拼接变体,导致一些病例在遗传上未被诊断出来.
在MYBPC3中的内源变异与HCM病原发生有关,但需要进一步的功能性研究.

研究的目的:

研究内在MYBPC3变异对mRNA拼接和心肌细胞功能的功能影响.
生成和表征诱导多能干细胞 (iPSC) 线,携带特定的内源性HCM相关变异.
探索不同的mRNA处理和质量控制对不同内部变异的反应的差异.

主要方法:

使用非整合性重编程策略生成患者衍生的iPSC线.
将iPSCs分化为iPSC衍生的心肌细胞 (iPSC-CMs).
对mRNA拼接模式的分析和对iPSC-CMs无意中介衰变 (NMD) 激活的评估.

主要成果:

在具有内在MYBPC3变异的iPSC-CM中识别了错误拼接的mRNA (c.1224-52G>A和c.1898-23A>G).
这两种变异都导致过早终止的编码子 (PTC),但只有c.1224-52G>A转录引发了NMD介导的降解.
c.1898-23A>G变异导致了脱离NMD的转录,可能导致截断的蛋白质生产.

结论:

内部MYBPC3变种可以通过异常的mRNA拼接和差异性NMD通路参与引起HCM.
生成的iPSC线是研究HCM内基变异的功能后果的关键工具.
这些iPSC模型为开发针对遗传性心肌病的拼接异常的治疗策略提供了一个平台.

关键词:

过度缩性心肌病变性是一种心脏病变.在MYBPC3中,您可以使用MYBPC3.非正规的拼接变体这就是 iPSC 的意义.

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