| 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. |
| Authors | Lisa B Cronk, Bin Ye, Toshihiko Kaku, David J Tester, Matteo Vatta, Jonathan C Makielski, Michael J Ackerman
(Affiliation: Mayo Medical School, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.)
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| Journal | Heart rhythm : the official journal of the Heart Rhythm Society
(Heart Rhythm)
Vol. 4
Issue 2
Pg. 161-6
(Feb 2007)
ISSN: 1547-5271 United States |
| PMID | 17275750
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- CAV3 protein, human
- Caveolin 3
- Sodium Channels
|
| Topics |
- 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)
|
