A Novel BHLHE41 Variant is Associated with Short Sleep and Resistance to Sleep Deprivation in Humans
A Novel BHLHE41 Variant is Associated with Short Sleep and Resistance to Sleep Deprivation in Humans
复制标题
DOI：
10.5665/sleep.3924
复制
发表时间：
2014-08-01
期刊：
影响因子：
5.6
通讯作者：
Pack, Allan I.
中科院分区：
文献类型：
--
作者：
Pellegrino, Renata;Kavakli, Ibrahim Halil;Pack, Allan I.
研究目的：早期的工作描述了DEC2的一个突变，也被称为BHLHE41(基本螺旋-环-螺旋家族成员E41)，是一个短睡者家庭的原因，这些人每晚只需要6小时的睡眠。设计：BHLHE41基因的测序、脑电数据、Delta功率分析和基于细胞的荧光素酶的功能研究。结果：我们在两个患有急性睡眠剥夺(n=200)或慢性部分睡眠剥夺(n=217)的队列中发现了BHLHE41基因的新变体。位于同一外显子另一个位置的变异Y362H出现在一对异卵双胞胎中的一个双胞胎中，与睡眠时间缩短、睡眠剥夺后恢复睡眠更少、睡眠剥夺期间表现减退有关。两对双胞胎的非快速眼动(NREM)睡眠时间几乎相同。该突变降低了BHLHE41体外抑制Clock/BMAL1和NPAS2/BMAL1反式激活的能力。同一外显子组中的另一个变异体对睡眠或睡眠剥夺的反应没有影响，对Clock/BMAL1反式激活也没有影响。随机突变鉴定出BHLHE41的其他一些影响其功能的变异体。突变减少了总睡眠，同时保持了NREM睡眠，并提供了对睡眠丧失的影响的抵抗力。影响睡眠的突变也改变了BHLHE41对CLOCK/BMAL1反式激活的正常抑制。因此，时钟机制可能与设定睡眠长度和睡眠内稳态的大小有关。
Study Objectives: Earlier work described a mutation in DEC2 also known as BHLHE41 (basic helix-loop-helix family member e41) as causal in a family of short sleepers, who needed just 6 h sleep per night. We evaluated whether there were other variants of this gene in two well-phenotyped cohorts.Design: Sequencing of the BHLHE41 gene, electroencephalographic data, and delta power analysis and functional studies using cell-based luciferase.Results: We identified new variants of the BHLHE41 gene in two cohorts who had either acute sleep deprivation (n = 200) or chronic partial sleep deprivation (n = 217). One variant, Y362H, at another location in the same exon occurred in one twin in a dizygotic twin pair and was associated with reduced sleep duration, less recovery sleep following sleep deprivation, and fewer performance lapses during sleep deprivation than the homozygous twin. Both twins had almost identical amounts of non rapid eye movement (NREM) sleep. This variant reduced the ability of BHLHE41 to suppress CLOCK/BMAL1 and NPAS2/BMAL1 transactivation in vitro. Another variant in the same exome had no effect on sleep or response to sleep deprivation and no effect on CLOCK/BMAL1 transactivation. Random mutagenesis identified a number of other variants of BHLHE41 that affect its function.Conclusions: There are a number of mutations of BHLHE41. Mutations reduce total sleep while maintaining NREM sleep and provide resistance to the effects of sleep loss. Mutations that affect sleep also modify the normal inhibition of BHLHE41 of CLOCK/BMAL1 transactivation. Thus, clock mechanisms are likely involved in setting sleep length and the magnitude of sleep homeostasis.