Nature genetics—KCNK3基因的功能获得性突变可引起睡眠呼吸暂停综合征：钾离子通道亢进和OSA的密切关联

中文摘要

睡眠呼吸暂停是一种危害全球公共健康的常见疾病。KCNK3编码TASK-1，一种与呼吸控制有关的K+通道，但其与睡眠呼吸暂停的关系尚不清楚。在这里，研究人员描述了一种与睡眠呼吸暂停相关的新的发育障碍（睡眠呼吸暂停的发育延迟，或DDSA），由KCNK3中罕见的新发功能获得性突变引起。这些突变聚集在“X门”周围，而“X门”是一种控制通道开放的门控模体。该突变因不再被G蛋白偶联受体通路所抑制，故表现为通道的过度亢进。然而，尽管X门控功能出现了缺陷，这些突变通道仍然可以被一系列已知的TASK通道抑制剂抑制。这些结果不仅突出了TASK-1 K+通道的重要新作用及其与睡眠呼吸暂停的关系，而且还鉴定出了可能的治疗策略。

英文摘要

Sleep apnea is a common disorder that represents a global public health burden. KCNK3 encodes TASK-1, a K+ channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Here we describe a new developmental disorder with associated sleep apnea (developmental delay with sleep apnea, or DDSA) caused by rare de novo gain-of-function mutations in KCNK3. The mutations cluster around the 'X-gate', a gating motif that controls channel opening, and produce overactive channels that no longer respond to inhibition by G-protein-coupled receptor pathways. However, despite their defective X-gating, these mutant channels can still be inhibited by a range of known TASK channel inhibitors. These results not only highlight an important new role for TASK-1 K+ channels and their link with sleep apnea but also identify possible therapeutic strategies.

参考文献：Gain-of-function mutations in KCNK3 cause a developmental disorder with sleep apnea.Nat Genet. 2022 Oct;54(10):1534-1543.

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