Published online before print October 23, 2006, doi: 10.1161/CIRCULATIONAHA.106.635268
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(Circulation. 2006;114:2104-2112.)
© 2006 American Heart Association, Inc.
Arrhythmia/Electrophysiology |
Mutant Caveolin-3 Induces Persistent Late Sodium Current and Is Associated With Long-QT Syndrome
From the Department of Pediatrics (Cardiology), Baylor College of Medicine, Texas Children’s Hospital, Houston (M.V., E.E.U., E.W.T., Z.L., J.A.T.); Departments of Internal Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics, Divisions of Cardiovascular Diseases and Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, Minn (M.J.A., D.J.T.); and Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin, Madison (B.Y., J.C.M., R.C.B., J.D.F., T.J.K.).
Correspondence to Matteo Vatta, PhD, Pediatrics (Cardiology), Baylor College of Medicine, Texas Children’s Hospital, 6621 Fannin St, FC 430.09, Houston, TX 77030 (e-mail mvatta{at}bcm.tmc.edu); or Michael J. Ackerman, MD, PhD, Sudden Death Genomics Laboratory, Guggenheim 501, Mayo Clinic College of Medicine, Rochester, MN 55905 (e-mail ackerman.michael@mayo.edu).
Received April 21, 2006; revision received August 29, 2006; accepted September 1, 2006.
Background— Congenital long-QT syndrome (LQTS) is a primary arrhythmogenic syndrome stemming from perturbed cardiac repolarization. LQTS, which affects 
1 in 3000 persons, is 1 of the most common causes of autopsy-negative sudden death in the young. Since the sentinel discovery of cardiac channel gene mutations in LQTS in 1995, hundreds of mutations in 8 LQTS susceptibility genes have been identified. All 8 LQTS genotypes represent primary cardiac channel defects (ie, ion channelopathy) except LQT4, which is a functional channelopathy because of mutations in ankyrin-B. Approximately 25% of LQTS remains unexplained pathogenetically. We have pursued a "final common pathway" hypothesis to elicit novel LQTS-susceptibility genes. With the recent observation that the LQT3-associated, SCN5A-encoded cardiac sodium channel localizes in caveolae, which are known membrane microdomains whose major component in the striated muscle is caveolin-3, we hypothesized that mutations in caveolin-3 may represent a novel pathogenetic mechanism for LQTS.
Methods and Results— Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, we performed open reading frame/splice site mutational analysis on CAV3 in 905 unrelated patients referred for LQTS genetic testing. CAV3 mutations were engineered by site-directed mutagenesis and the molecular phenotype determined by transient heterologous expression into cell lines that stably express the cardiac sodium channel hNav1.5. We identified 4 novel mutations in CAV3-encoded caveolin-3 that were absent in >1000 control alleles. Electrophysiological analysis of sodium current in HEK293 cells stably expressing hNav1.5 and transiently transfected with wild-type and mutant caveolin-3 demonstrated that mutant caveolin-3 results in a 2- to 3-fold increase in late sodium current compared with wild-type caveolin-3. Our observations are similar to the increased late sodium current associated with LQT3-associated SCN5A mutations.
Conclusions— The present study reports the first CAV3 mutations in subjects with LQTS, and we provide functional data demonstrating a gain-of-function increase in late sodium current.
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