Mutant Caveolin-3 Induces Persistent Late Sodium Current and Is Associated With Long-QT Syndrome

• DOI: 10.1161/circulationaha.106.635268
• Publication Date: 2006-10-24T14:16:50Z
• Authors: Matteo Vatta; Michael J. Ackerman; Bin Ye; Jonathan C. Makie...; Enoh E. Ughanze; Erica W. Taylor; David J. Tester; Ravi C. Balijepalli; Jason D. Foell; Zhaohui Li; Timothy J. Kamp; Jeffrey A. Towbin
• Keywords: Caveolin 3; Channelopathy

Background— Congenital long-QT syndrome (LQTS) is a primary arrhythmogenic stemming from perturbed cardiac repolarization. LQTS, which affects ≈1 in 3000 persons, 1 of the most common causes autopsy-negative sudden death young. Since sentinel discovery channel gene mutations LQTS 1995, hundreds 8 susceptibility genes have been identified. All genotypes represent defects (ie, ion channelopathy) except LQT4, functional channelopathy because ankyrin-B. Approximately 25% remains unexplained pathogenetically. We pursued “final pathway” hypothesis to elicit novel LQTS-susceptibility genes. With recent observation that LQT3-associated, SCN5A -encoded sodium localizes caveolae, are known membrane microdomains whose major component striated muscle caveolin-3, we hypothesized caveolin-3 may pathogenetic mechanism for LQTS. Methods and Results— Using polymerase chain reaction, denaturing high-performance liquid chromatography, direct DNA sequencing, performed open reading frame/splice site mutational analysis on CAV3 905 unrelated patients referred genetic testing. were engineered by site-directed mutagenesis molecular phenotype determined transient heterologous expression into cell lines stably express hNa v 1.5. identified 4 absent >1000 control alleles. Electrophysiological current HEK293 cells expressing 1.5 transiently transfected with wild-type mutant demonstrated results 2- 3-fold increase late compared caveolin-3. Our observations similar increased associated LQT3-associated mutations. Conclusions— The present study reports first subjects provide data demonstrating gain-of-function current.