Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome
Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome
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DOI：
10.1038/nature03453
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发表时间：
2005-03-31
期刊：
影响因子：
64.8
通讯作者：
Fu, YH
中科院分区：
文献类型：
--
作者：
Xu, Y;Padiath, QS;Fu, YH
家族性睡眠时相提前综合征 (FASPS) 是一种以早睡和早醒为特征的人类行为表型 (1)。它是第一个被充分表征的人类孟德尔昼夜节律变异，并被证明是由人类 PER2 基因酪蛋白激酶 I (CKI) 结合域内的磷酸化位点突变引起的。为了更深入地了解人类昼夜节律调节机制，我们着手鉴定人类受试者中导致 FAPSS 的突变。我们在这里报告了人类 CKI delta 基因中错义突变 (T44A) 的鉴定，该突变导致 FAPSS。这种突变激酶在体外降低了酶活性。携带人类CKI delta-T44A基因的转基因果蝇表现出昼夜节律周期延长的表型。相比之下，携带相同突变的转基因小鼠的昼夜节律周期较短，其表型类似于人类 FASPS。这些结果表明，CKI delta 是哺乳动物生物钟的核心组成部分，并表明哺乳动物和果蝇生物钟可能具有不同的调节机制，尽管它们的各个组成部分具有高度保守的性质。
Familial advanced sleep phase syndrome (FASPS) is a human behavioural phenotype characterized by early sleep times and early-morning awakening(1). It was the first human, mendelian circadian rhythm variant to be well-characterized, and was shown to result from a mutation in a phosphorylation site within the casein kinase I (CKI)-binding domain of the human PER2 gene. To gain a deeper understanding of the mechanisms of circadian rhythm regulation in humans, we set out to identify mutations in human subjects leading to FASPS. We report here the identification of a missense mutation (T44A) in the human CKI delta gene, which results in FASPS. This mutant kinase has decreased enzymatic activity in vitro. Transgenic Drosophila carrying the human CKI delta-T44A gene showed a phenotype with lengthened circadian period. In contrast, transgenic mice carrying the same mutation have a shorter circadian period, a phenotype mimicking human FASPS. These results show that CKI delta is a central component in the mammalian clock, and suggest that mammalian and fly clocks might have different regulatory mechanisms despite the highly conserved nature of their individual components.