一种新的BAG5变体损害了ER应激反应途径,导致扩张性心肌病和心律失常
Rutairat Wongong1,2, Anusak Kijtawornrat3, Chalurmpon Srichomthong2
1Center of Excellence for Medical Genomics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Scientific reports
|May 25, 2024
概括
一种新型的BAG5基因突变通过破坏内分泌网膜 (ER) 应激反应,导致严重扩张性心肌病 (DCM). 这项研究还发现,受影响的雄性小鼠中心律不整的发生有性别特异性.
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
- 细胞内膜网膜应激压力
背景情况:
- 最近,BAG5基因的致病变体与扩张性心肌病 (DCM) 相关.
- 需要进一步的研究来了解BAG5相关的DCM的表型,突变和病理机制方面.
- 细胞内膜网膜 (ER) 的压力与各种心脏病理有关.
研究的目的:
- 研究与BAG5变异相关的DCM的临床和分子特征.
- 探索BAG5变异对心脏ER应激反应的影响.
- 为了识别 BAG5 新型突变,并阐明它们在 DCM 病原发生中的作用.
主要方法:
- 对疑似DCM的受影响和未受影响的家庭成员进行临床评估.
- 整体外体和桑格测序以识别遗传变异.
- 在压力条件下的Bag5淘汰赛和淘汰赛小鼠模型的生成和生理评估 (图尼卡米辛的使用).
主要成果:
- 在患有严重DCM和心律失常的兄弟姐妹中发现了一种新的同卵性BAG5变体 (c.444_445delGA).
- 在ER应激诱导后,缺乏Bag5的小鼠表现出心脏功能受损 (减少LVFS和LVEF) 和亡增加.
- 雄性Bag5缺陷小鼠表现出性别特异性心律失常,在Bag5-/-中比Bag5+/-小鼠更明显.
结论:
- 一个新的BAG5突变通过受损的ER应激反应引起DCM.
- 在ER压力下,BAG5缺乏导致心脏功能障碍和亡.
- 在BAG5缺乏的雄性小鼠中,在心律失常易感性中观察到性别特异性差异.
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