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Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome.


BACKGROUND: Congenital long-QT syndrome (LQTS) is a primary arrhythmogenic syndrome stemming from perturbed cardiac repolarization. LQTS, which affects approximately 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 hNa(v)1.5. 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 hNa(v)1.5 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.

Pubmed ID: 17060380


  • Vatta M
  • Ackerman MJ
  • Ye B
  • Makielski JC
  • Ughanze EE
  • Taylor EW
  • Tester DJ
  • Balijepalli RC
  • Foell JD
  • Li Z
  • Kamp TJ
  • Towbin JA



Publication Data

November 14, 2006

Associated Grants

  • Agency: NHLBI NIH HHS, Id: P01 HL47053
  • Agency: NICHD NIH HHS, Id: R01 HD42569
  • Agency: NHLBI NIH HHS, Id: R01 HL71092
  • Agency: NHLBI NIH HHS, Id: R21HL077706
  • Agency: NHLBI NIH HHS, Id: R21HL078807
  • Agency: NHLBI NIH HHS, Id: U01-HL65652

Mesh Terms

  • Amino Acid Sequence
  • Caveolin 3
  • Cell Line
  • DNA Mutational Analysis
  • Electric Conductivity
  • Electrocardiography
  • Electrophysiology
  • Female
  • Humans
  • Immunoprecipitation
  • Long QT Syndrome
  • Male
  • Molecular Sequence Data
  • Muscle Proteins
  • Mutation
  • Myocardium
  • NAV1.5 Voltage-Gated Sodium Channel
  • Sodium Channels
  • Time Factors
  • Transfection