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.
Andersen-Tawil Syndrome (ATS) is a rare Mendelian form of periodic paralysis and cardiac arrhythmia with developmental features for which we cloned one ATS gene and showed that it is mutated in ~2/3 of ATS patients-the remaining unexplained ATS families need to be characterized at a genetic and molecular level and efforts in this direction are limited by the sporadic nature of ATS in many cases or the small size of most families with ATS. We propose to employ whole exome sequencing for the identification of a second ATS gene as such work will aid in diagnosis of these patients and may identify novel targets for therapeutic development for this membrane excitability disorder and perhaps others like migraine and epilepsy. We've also generated a genetic model of several ATS1 mutations (in the potassium channel KCNJ2) and will begin characterizing the muscle and developmental phenotypes to gain better insights into pathophysiology.
|Ptá?ek, Louis J (2015) Episodic disorders: channelopathies and beyond. Annu Rev Physiol 77:475-9|
|Lee, Hsien-yang; Fu, Ying-Hui; Ptá?ek, Louis J (2015) Episodic and electrical nervous system disorders caused by nonchannel genes. Annu Rev Physiol 77:525-41|