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

Heart Rhythm. 2007 Feb;4(2):161-6. doi: 10.1016/j.hrthm.2006.11.030. Epub 2006 Dec 6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caveolin 3 / genetics*
  • Cell Line
  • Chromatography, High Pressure Liquid
  • DNA Mutational Analysis
  • Electrophysiologic Techniques, Cardiac
  • Female
  • Humans
  • Infant
  • Long QT Syndrome / genetics*
  • Male
  • Mutation, Missense / genetics*
  • Phenotype
  • Polymerase Chain Reaction
  • Sodium Channels / genetics*
  • Sudden Infant Death / genetics*


  • CAV3 protein, human
  • Caveolin 3
  • Sodium Channels