Genetic and molecular pathophysiology of ATS

 描述(由申请人提供) Andersen-Tawil综合征(ATS)是家族性周期性麻痹(FPP)之一。它在这一组中的其他疾病中脱颖而出，因为它是一种多系统疾病。安徒生在1971年首次报告了一个病例，该病例有发作性虚弱、心律失常以及面部、头部和四肢远端的发育特征。在过去的二十年里，我们对250多名ATS患者进行了特征描述，并对这种疾病的这三个方面进行了详细的分类(1-3)。此外，我们量化了发育表型，并描述了该疾病的其他特征，包括牙科和神经认知表型特征(4，5)。我们克隆了一个基因(KCNJ2)，该基因在大约65%的ATS家族中发生突变(6)。大多数KCNJ2突变被认为影响与PIP2的结合并关闭钾通道(7)，但这如何导致ATS的多系统疾病仍不清楚。我们继续在体外表征患者引起的突变的生理后果，最近产生了一只携带KCNJ2突变的小鼠。当前提案的主要目的是识别第二个ATS基因，并在其余原因不明的患者中识别导致ATS的突变。确定第二个基因的因果突变将极大地促进我们对ATS病因学的理解。此外，这可能有助于更好地了解正常的肌肉生理学。

 DESCRIPTION (provided by applicant) Andersen-Tawil Syndrome (ATS) is one of the familial periodic paralyses (FPP). It stands out among the other disorders in this group in that it is a multisystem disease. Andersen first reported a single case in 1971 that had episodic weakness, cardiac arrhythmias, and developmental features of the face, head, and distal limbs. Over the last two decades, we have characterized over 250 patients with ATS and laid down a detailed classification for these three aspects of this disorder (1-3). In addition, we have quantified the developmental phenotype and described additional features of the disorder including dental and neurocognitive phenotypes characteristic for this disorder (4, 5). We cloned a gene (KCNJ2) that is mutated in approximately 65% of all ATS families (6). The majority of the KCNJ2 mutations are believed to affect binding to PIP2 and close the potassium channel (7), but how this may cause the multisystem disease of ATS is still not clear. We've gone on to characterize the physiological consequences of patient-causing mutations in vitro and more recently generated a mouse carrying mutations of KCNJ2. The major thrust of the current proposal is to identify a second ATS gene and identify mutations causing ATS in the remaining unexplained patients. Identifying causal mutations in a second gene will greatly advance our understanding of the etiology of ATS. In addition, it may lead to better understanding of normal muscle physiology.