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

Matteo Vatta, Michael J. Ackerman, Bin Ye, Jonathan C. Makielski, Enoh E. Ughanze, Erica W. Taylor, David J. Tester, Ravi C. Balijepalli, Jason D. Foell, Zhaohui Li, Timothy J. Kamp, Jeffrey Towbin

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2104-2112
Number of pages9
JournalCirculation
Volume114
Issue number20
DOIs
StatePublished - Nov 1 2006

Fingerprint

Caveolin 3
Long QT Syndrome
Sodium
Mutation
Channelopathies
Sodium Channels
Ankyrins
Membrane Microdomains
Genes
Caveolae
Striated Muscle
HEK293 Cells
Genetic Testing
Sudden Death
Site-Directed Mutagenesis
DNA Sequence Analysis
Open Reading Frames
Autopsy

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Vatta, M., Ackerman, M. J., Ye, B., Makielski, J. C., Ughanze, E. E., Taylor, E. W., ... Towbin, J. (2006). Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation, 114(20), 2104-2112. https://doi.org/10.1161/CIRCULATIONAHA.106.635268

Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. / Vatta, Matteo; Ackerman, Michael J.; Ye, Bin; Makielski, Jonathan C.; Ughanze, Enoh E.; Taylor, Erica W.; Tester, David J.; Balijepalli, Ravi C.; Foell, Jason D.; Li, Zhaohui; Kamp, Timothy J.; Towbin, Jeffrey.

In: Circulation, Vol. 114, No. 20, 01.11.2006, p. 2104-2112.

Research output: Contribution to journalArticle

Vatta, M, Ackerman, MJ, Ye, B, Makielski, JC, Ughanze, EE, Taylor, EW, Tester, DJ, Balijepalli, RC, Foell, JD, Li, Z, Kamp, TJ & Towbin, J 2006, 'Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome', Circulation, vol. 114, no. 20, pp. 2104-2112. https://doi.org/10.1161/CIRCULATIONAHA.106.635268
Vatta M, Ackerman MJ, Ye B, Makielski JC, Ughanze EE, Taylor EW et al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation. 2006 Nov 1;114(20):2104-2112. https://doi.org/10.1161/CIRCULATIONAHA.106.635268
Vatta, Matteo ; Ackerman, Michael J. ; Ye, Bin ; Makielski, Jonathan C. ; Ughanze, Enoh E. ; Taylor, Erica W. ; Tester, David J. ; Balijepalli, Ravi C. ; Foell, Jason D. ; Li, Zhaohui ; Kamp, Timothy J. ; Towbin, Jeffrey. / Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. In: Circulation. 2006 ; Vol. 114, No. 20. pp. 2104-2112.
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AU - Vatta, Matteo

AU - Ackerman, Michael J.

AU - Ye, Bin

AU - Makielski, Jonathan C.

AU - Ughanze, Enoh E.

AU - Taylor, Erica W.

AU - Tester, David J.

AU - Balijepalli, Ravi C.

AU - Foell, Jason D.

AU - Li, Zhaohui

AU - Kamp, Timothy J.

AU - Towbin, Jeffrey

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N2 - 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.

AB - 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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