在LRRC8C中产生构成性通道激活的de novo变异会导致人类多系统性疾病
Mathieu Quinodoz1,2,3, Sonja Rutz4, Virginie Peter1,2
1Institute of Molecular and Clinical Ophthalmology Basel (IOB), 4031, Basel, Switzerland.
The EMBO journal
|December 2, 2024
概括
在LRRC8C基因中的致病变体导致体积调节阳离子通道 (VRACs) 的功能增益突变. 这些突变导致通道过度活跃,是影响多个器官的先天性综合征的基础.
科学领域:
- 分子生物学分子生物学
- 遗传学 遗传学 是一个
- 生理学 生理学 生理学
背景情况:
- 由LRRC8家族蛋白质组成的体积调节离子通道 (VRACs) 被低压胀激活.
- VRACs的特定功能和疾病相关性,特别是LRRC8C,仍然在很大程度上是未知的.
研究的目的:
- 研究在患有先天性综合征的患者中发现的新型LRRC8C变异的功能后果.
- 阐明这种新型临床实体中VRAC功能障碍背后的分子机制.
主要方法:
- 低温电子显微镜 (cryo-EM) 用于分析LRRC8C突变蛋白质结构.
- 通过与LRRC8A共同表达野生型和突变LRRC8C来对VRACs进行功能性表征.
- 对新出现LRRC8C变异的患者进行临床评估.
主要成果:
- 在两名患有影响血管,大脑,眼睛和骨的综合征的患者中发现了LRRC8C的de novo变异.
- 结冷EM显示LRRC8C突变蛋白质的灵活性增加,表明不稳定的子单元相互作用.
- 突变的LRRC8C通道显示了增强的激活,即使在同位素条件下也表现出活性.
结论:
- 在LRRC8C中的结构性干扰会损害通道封闭,导致主导的功能增益效应.
- 这些发现确定了LRRC8C变体,VRAC功能障碍和复杂的先天性综合征之间的机制联系.
- 该研究强调了VRAC在各种组织和器官中的关键作用.
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