The role of CAV3 gene in channelopathies

Congenital long-QT syndrome (LQTS) is a hereditary cardiac disease characterized by a high risk of life-threatening arrhythmias. Until recently, LQTS was exclusively a cardiac channelopathy. It was observed that the LQT3 associated, SCN5A-encoded cardiac sodium channel localizes in caveolae and it was hypothesized that mutations in caveolin-3 may represent a novel pathogenetic mechanism for LQTS (LQT9). Caveolae are characterized by the presence of caveolins, scaffolding proteins that interact with cholesterol and provide the structural framework for macromolecular signaling complexes. Using polymerase chain reaction and direct DNA sequencing, mutational analysis on CAV3 gene was performed on DNA extracted from 50 patients with LQTS diagnosis, but with no mutations on the entire coding regions of the major LQTS associated genes – KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and KCNJ2 – and targeted analysis of ANK2 and RyR2. Mutational analysis of CAV3 in 50 unrelated LQTS subjects identified 9 mutations; two of them were found in the coding region. They are missense mutations and are located in a very conserved region. Mutations in the intronic sequences were analyzed by SpliceAid (www.introni.it), a web resource to predict the effect of the DNA mutations at the level of the target sequences of the RNA-binding proteins that determine the pattern of mRNA splicing. Some of them may alter the correct mRNA splicing. Further studies are needed to characterize the impact of these mutations in vivo.