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Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome

机译：CKIδ突变导致家族性晚期睡眠相综合征的功能后果

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Familial advanced sleep phase syndrome (FASPS) is a human behavioural phenotype characterized by early sleep times and early-morning awakening. 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 CKIδ gene, which results in FASPS. This mutant kinase has decreased enzymatic activity in vitro. Transgenic Drosophila carrying the human CKIδ-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 CKIδ 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.
机译：家族性晚期睡眠阶段综合征（FASPS）是一种人类行为表型，其特征在于早睡时间和早醒。它是第一个特征明确的人类孟德尔昼夜节律变体，并显示是由于人类PER2基因的酪蛋白激酶I（CKI）结合域内的磷酸化位点发生突变而引起的。为了更深入地了解人类的昼夜节律调节机制，我们着手鉴定导致FASPS的人类受试者突变。我们在此报告了人类CKIδ基因中导致FASPS的错义突变（T44A）的鉴定。该突变型激酶在体外具有降低的酶活性。携带人类CKIδ-T44A基因的转基因果蝇表现出昼夜周期延长的表型。相比之下，带有相同突变的转基因小鼠的昼夜节律周期较短，这是模仿人FASPS的表型。这些结果表明，CKIδ是哺乳动物钟中的重要组成部分，表明尽管哺乳动物钟和果蝇钟的各个成分高度保守，但它们可能具有不同的调节机制。

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