Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder.
Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder.
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DOI：
10.1016/j.cell.2017.03.027
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发表时间：
2017-04-06
期刊：
影响因子：
64.5
通讯作者：
Young MW
中科院分区：
文献类型：
--
作者：
Patke A;Murphy PJ;Onat OE;Krieger AC;Özçelik T;Campbell SS;Young MW
人类日常活动的模式是由内在的生物钟控制的，它在许多行为和生理过程中促进24小时的节律。该系统在延迟睡眠阶段障碍（DSPD）中发生改变，这是一种常见的失眠形式，睡眠发作转移到与社会规范不一致的晚些时候。在这里，我们报告了DSPD的遗传形式与核心生物钟基因CRY1的显性编码变异相关，该变异产生了一种转录抑制剂，对昼夜节律激活蛋白clock和Bmal1具有增强的亲和力。这种功能获得的CRY1变体导致关键转录靶点的表达减少，并延长昼夜分子节律的周期，从而提供了与DSPD症状的机制联系。该等位基因的频率高达0.6%，非相关家族的反向表型证实了携带者的晚睡和/或碎片化睡眠模式，这表明它影响了相当一部分人的睡眠行为。人类生物钟基因CRY1的变异与家族形式的延迟睡眠阶段障碍有关，为“夜猫子”提供了遗传基础。
Patterns of daily human activity are controlled by an intrinsic circadian clock that promotes ~24 hour rhythms in many behavioral and physiological processes. This system is altered in Delayed Sleep Phase Disorder (DSPD), a common form of insomnia where sleep episodes are shifted to later times misaligned with the societal norm. Here, we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele has a frequency of up to 0.6% and reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers, suggesting that it affects sleep behavior in a sizeable portion of the human population. A variation in the human circadian clock gene CRY1 is associated with a familial form of Delayed Sleep Phase Disorder, providing genetic underpinnings for “night owls”.