A de novo mutation in Caveolin-3 gene may confer genetic susceptibility to Long QT syndrome

Abstract Long-QT syndrome (LQTS) is a potentially lethal, inheritable arrhyithmia disorder, stemming from perturbed cardiac repolarization and affecting about 1 in 3000 persons. The pathogenetic basis for LQTS has focused on ion channels. Recently, 2 LQTS-susceptibility genes encoding for two non-ion channel proteins have been discovered. The first gene encodes an adapter protein, ankyrin B, which participates in localization of sodium and calcium channels to the sarcolemma; the second one encodes Caveolin-3, the major scaffolding protein present in caveolae in the heart: mutations in both genes result in secondarily ion channels disruption as consequence of altered localization or function [1,2]. Caveolin-3 is involved in multiple cellular processes, including vesicular transport, cholesterol and calcium homeostasis, and signal transduction [3,4], playing a diverse and critical role in the cardiovascular system [5]. Caveolin-3 functions as chaperons and scaffolds protein recruiting signaling molecules to caveolae, providing direct temporal and spatial regulation of signal transduction [3,6]. In particular, Caveolin-3 can interact and modulate the activity of ERK 1/2 [5,7]. In the heart ERK 1/2 control a complex network of regulatory mechanisms that protect cardiomyocytes against different stresses (such as hypoxia, ischemia–reperfusion, hyperosmotic and oxidative stress) that ultimately lead to cellular disfunction and death [8,9]. Therefore, aberrant cellular stress responses are potentially relevant to the development of arrhythmias and such mechanisms may play a significantly role in LQTS secondarily to Caveolin-3 alteration.