Genetic and molecular pathophysiology of ATS

University Of California, San Francisco, San Francisco CA

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Abstract

? 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.