甲状腺毒症性周期性瘫痪的致病基因及发病机制探索

Thyrotoxic periodic paralysis (TPP) is one of the complications of thyrotoxicosis and is the most common cause of acute acquired paralysis in adults. Characterized by reversible muscle flaccidity and hypokalemia, TPP almost exclusively occurs in young thyrotoxic asian males. In the most severe cases, respiratory muscles could be affected and malignant cardiac arrhythmia could develop. It is assumed that thyrotoxicosis, high androgen level, hyperinsulinemia and genetic susceptibility may all take part in the pathogenesis of TPP, though the exact mechanism is not known. Now we have finished the exome sequencing of 18 samples, and 12 genes are suspected to be pathogenic. Some genes are associated with muscle fiber, androgens, insulin and thyroid hormones, forming a complicated network among these factors. We highly suspect that the pathogenesis of TPP involves multiple factors and multiple genes in the network, which may lead to the increase of the activity of Na+, K+-ATPase and therefore hypokalemia and paralysis. Now we plan to verify the pathogenic genes by target region sequencing in a big sample, to confirm the pathogenic function of the genes and to explore the pathogenesis of TPP in human muscle cell models.

甲状腺毒症性周期性瘫痪(thyrotoxic periodic paralysis, TPP)是甲状腺毒症患者常见的并发症之一和成人急性获得性四肢瘫最常见的病因。它以突发肌无力伴低钾血症为特征，多发于亚洲青年男性甲亢患者，严重者可累及呼吸肌或引起恶性心律失常。学者们猜想甲状腺毒症、高雄激素水平、高胰岛素血症和基因易感性可能共同参与发病，但具体机制并不清楚。目前我们完成了共18例样本的外显子组测序，并锁定12个基因为可疑致病基因，其中部分基因在雄激素、胰岛素、甲状腺激素和肌蛋白之间构建了一个复杂的网络。我们高度怀疑TPP的发作是多基因与多因素通过上述网络模式共同作用，增加Na+, K+-ATPase活性而导致低钾瘫痪的。现拟用目标区域捕获测序技术对可疑基因进行大样本验证，再通过人骨骼肌细胞模型进行功能学验证和TPP发病机制的探索。