Sci Transl Med：与睡眠有关的基因突变与偏头痛有关

据一项新的研究报告，一种会改变睡眠模式的酶也会改变大脑的活动并可能触发偏头痛。

这种被称作酪蛋白激酶的酶可能成为一种用来治疗这些使人衰弱的头痛的一种潜在标靶。脑中的异常活动会导致搏动性头痛并有时会触发恶心与呕吐。有些人还会感受到被称为偏头痛先兆的感觉功能障碍——如幻觉，畏光以及其他症状。Kevin Brennan及其同事发现，酪蛋白激酶改变多种脑蛋白活性的方式可能会产生偏头痛。研究人员对一个有偏头痛病史的家族进行了观察。该家族中许多家庭成员还患有一种叫做睡眠状态提前性障碍的睡眠疾病，它会破坏正常的睡眠模式，使得患者在晚上（6-8点）习惯性地入睡并在黎明前醒来。研究人员注意到这些睡眠问题是由酪蛋白激酶基因的一个突变引起的，这一突变会改变生物钟。这一突变也出现在了罹患偏头痛的人中。

文章的作者在他们的患者数据库中进行了搜寻并发现了另外一个家族，他们的酪蛋白激酶变异与偏头痛相关。接着，研究人员转而就酪蛋白激酶变异——当该酶在小鼠体内表达时——是否会在小鼠中引起偏头痛进行了测试。虽然很难判断小鼠是否会和人一样感受偏头痛，但研究人员发现，有酪蛋白激酶变异的小鼠显示出的脑部活动模式类似于在偏头痛患者中所见到的模式。尤其是，这些小鼠出现了被称为皮层扩散性抑制的脑波活动的增加，皮层扩散性抑制被认为会引起偏头痛先兆。像患有偏头痛的病人一样，这些小鼠也对光和噪音更加敏感。给这些小鼠用偏头痛药物进行治疗似乎可减少某些这样的症状。这些发现提示，酪蛋白激酶变异可能在偏头痛中起着某种作用。一则相关的《焦点》文章对这些发现进行了讨论。

doi:10.1126/scitranslmed.3005784
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Casein Kinase Iδ Mutations in Familial Migraine and Advanced Sleep Phase

K. C. Brennan, Emily A. Bates, Robert E. Shapiro, Jekaterina Zyuzin, William C. Hallows, Yong Huang, Hsien-Yang Lee, Christopher R. Jones, Ying-Hui Fu, Andrew C. Charles and Louis J. Ptácek

Migraine is a common disabling disorder with a significant genetic component, characterized by severe headache and often accompanied by nausea, vomiting, and light sensitivity. We identified two families, each with a distinct missense mutation in the gene encoding casein kinase Iδ (CKIδ), in which the mutation cosegregated with both the presence of migraine and advanced sleep phase. The resulting alterations (T44A and H46R) occurred in the conserved catalytic domain of CKIδ, where they caused reduced enzyme activity. Mice engineered to carry the CKIδ-T44A allele were more sensitive to pain after treatment with the migraine trigger nitroglycerin. CKIδ-T44A mice also exhibited a reduced threshold for cortical spreading depression (believed to be the physiological analog of migraine aura) and greater arterial dilation during cortical spreading depression. Astrocytes from CKIδ-T44A mice showed increased spontaneous and evoked calcium signaling. These genetic, cellular, physiological, and behavioral analyses suggest that decreases in CKIδ activity can contribute to the pathogenesis of migraine.