Gain-of-function mutations in KCNK3 cause a developmental disorder with sleep apnea.
Gain-of-function mutations in KCNK3 cause a developmental disorder with sleep apnea.
复制标题
KCNK3的功能性突变会导致睡眠呼吸暂停的发育障碍。
DOI：
10.1038/s41588-022-01185-x
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发表时间：
2022-10
期刊：
影响因子：
30.8
通讯作者：
Tucker, Stephen J.
中科院分区：
文献类型：
--
作者：
Sormann, Janina;Schewe, Marcus;Proks, Peter;Jouen-Tachoire, Thibault;Rao, Shanlin;Riel, Elena B.;Agre, Katherine E.;Begtrup, Amber;Dean, John;Descartes, Maria;Fischer, Jan;Gardham, Alice;Lahner, Carrie;Mark, Paul R.;Muppidi, Srikanth;Pichurin, Pavel N.;Porrmann, Joseph;Schallner, Jens;Smith, Kirstin;Straub, Volker;Vasudevan, Pradeep;Willaert, Rebecca;Carpenter, Elisabeth P.;Rodstrom, Karin E. J.;Hahn, Michael G.;Mueller, Thomas;Baukrowitz, Thomas;Hurles, Matthew E.;Wright, Caroline F.;Tucker, Stephen J.
睡眠呼吸暂停是一种常见的疾病，是全球公共卫生负担。KCNK 3编码了与呼吸控制有关的K+通道，但其与睡眠呼吸暂停的联系仍然知之甚少。在这里，我们描述了一种新的发育障碍与相关的睡眠呼吸暂停（发育迟缓与睡眠呼吸暂停，或DDSA）所造成的罕见的从头功能获得性突变KCNK 3。这些突变聚集在“X门”周围，这是一种控制通道开放的门控基序，并产生过度活跃的通道，不再对G蛋白偶联受体途径的抑制反应。然而，尽管它们有缺陷的X门控，这些突变通道仍然可以被一系列已知的ASK通道抑制剂抑制。这些结果不仅突出了一个重要的新作用，任务-1 K+通道及其与睡眠呼吸暂停的联系，但也确定了可能的治疗策略。编码双孔结构域K+通道ASK-1的KCNK 3中的杂合从头功能获得性突变导致以发育延迟伴睡眠呼吸暂停为特征的通道病。
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. Heterozygous de novo gain-of-function mutations in KCNK3, which encodes the two-pore-domain K+ channel TASK-1, cause a channelopathy characterized by developmental delay with sleep apnea.
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影响因子：
16.6
作者：
Aryal, Prafulla;Abd-Wahab, Firdaus;Bucci, Giovanna;Sansom, Mark S. P.;Tucker, Stephen J.
通讯作者：
Tucker, Stephen J.
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通讯作者：
Bayliss DA
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通讯作者：
Kim, DH
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通讯作者：
Rump, Andreas
影响因子：
76.2
作者：
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通讯作者：
Malhotra, Atul