钾通道 Kir2.6 突变导致甲状腺毒性低钾周期性瘫痪易感性。
Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis.
机构信息
Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, 94158, USA.
出版信息
Cell. 2010 Jan 8;140(1):88-98. doi: 10.1016/j.cell.2009.12.024.
Thyrotoxic hypokalemic periodic paralysis (TPP) is characterized by acute attacks of weakness, hypokalemia, and thyrotoxicosis of various etiologies. These transient attacks resemble those of patients with familial hypokalemic periodic paralysis (hypoKPP) and resolve with treatment of the underlying hyperthyroidism. Because of the phenotypic similarity of these conditions, we hypothesized that TPP might also be a channelopathy. While sequencing candidate genes, we identified a previously unreported gene (not present in human sequence databases) that encodes an inwardly rectifying potassium (Kir) channel, Kir2.6. This channel, nearly identical to Kir2.2, is expressed in skeletal muscle and is transcriptionally regulated by thyroid hormone. Expression of Kir2.6 in mammalian cells revealed normal Kir currents in whole-cell and single-channel recordings. Kir2.6 mutations were present in up to 33% of the unrelated TPP patients in our collection. Some of these mutations clearly alter a variety of Kir2.6 properties, all altering muscle membrane excitability leading to paralysis.
甲状腺毒症性低钾周期性瘫痪（TPP）的特征是急性无力、低钾血症和各种病因的甲状腺毒症。这些短暂发作类似于家族性低钾周期性瘫痪（低钾性周期性瘫痪）患者的发作，随着基础甲状腺功能亢进的治疗而缓解。由于这些病症的表型相似，我们假设 TPP 也可能是一种通道病。在对候选基因进行测序时，我们发现了一个以前未报道的基因（不在人类序列数据库中），该基因编码一种内向整流钾（Kir）通道 Kir2.6。这种通道与 Kir2.2 几乎相同，在骨骼肌中表达，并受甲状腺激素的转录调控。在哺乳动物细胞中表达 Kir2.6 表明在全细胞和单通道记录中存在正常的 Kir 电流。我们收集的无关 TPP 患者中，多达 33%存在 Kir2.6 突变。其中一些突变显然改变了各种 Kir2.6 特性，所有这些特性都改变了肌肉膜的兴奋性，导致瘫痪。
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