Novel mechanism for sudden infant death syndrome: Persistent late sodium current secondary to mutations in caveolin-3

Lisa B. Cronk, Bin Ye, Toshihiko Kaku, David J. Tester, Matteo Vatta, Jonathan C. Makielski, Michael J. Ackerman

Research output: Contribution to journalArticlepeer-review

184 Scopus citations

Abstract

Background: Sudden infant death syndrome (SIDS) is one of the leading causes of death during the first year of life. Long QT syndrome (LQTS)-associated mutations may be responsible for 5% to 10% of SIDS cases. We recently established CAV3-encoded caveolin-3 as a novel LQTS-associated gene with mutations producing a gain-of-function, LQT3-like molecular/cellular phenotype. Objective: The purpose of this study was to determine the prevalence and functional properties of CAV3 mutations in SIDS. Methods: Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, postmortem genetic testing of CAV3 was performed on genomic DNA isolated from frozen necropsy tissue on a population-based cohort of unrelated cases of SIDS (N = 134, 57 females, average age = 2.7 months). CAV3 mutations were engineered using site-directed mutagenesis and heterologously expressed in HEK293 cell lines stably expressing the SCN5A-encoded cardiac sodium channel. Results: Overall, three distinct CAV3 mutations (V14L, T78M, and L79R) were identified in three of 50 black infants (6-month-old male, 2-month-old female, and 8 month-old female), whereas no mutations were detected in 83 white infants (P <.05). CAV3 mutations were more likely in decedents 6 months or older (2/12) than in infants who died before 6 months (1/124, P = .02). Voltage clamp studies showed that all three CAV3 mutations caused a significant fivefold increase in late sodium current compared with controls. Conclusion: This study provides the first molecular and functional evidence implicating CAV3 as a pathogenic basis of SIDS. The LQT3-like phenotype of increased late sodium current supports an arrhythmogenic mechanism for some cases of SIDS.

Original languageEnglish (US)
Pages (from-to)161-166
Number of pages6
JournalHeart rhythm
Volume4
Issue number2
DOIs
StatePublished - Feb 2007

Keywords

  • Caveolae
  • Caveolin
  • Genetics
  • Ion channels
  • Sudden death
  • Sudden infant death syndrome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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