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


CONCLUSIONS
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.
Cronk
Lisa B
LB
Mayo Medical School, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Ye
Bin
B
Kaku
Toshihiko
T
Tester
David J
DJ
Vatta
Matteo
M
Makielski
Jonathan C
JC
Ackerman
Michael J
MJ
D051244:Caveolin 3 / Q000235:genetics*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006801:Humans; D007223:Infant; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D015222:Sodium Channels / Q000235:genetics*; D013398:Sudden Infant Death / Q000235:genetics*
C417736:CAV3 protein, human; D051244:Caveolin 3; D015222:Sodium Channels