Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3.
Heart Rhythm
; 4(2): 161-6, 2007 Feb.
Article
em En
| MEDLINE
| ID: mdl-17275750
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Morte Súbita do Lactente
/
Síndrome do QT Longo
/
Canais de Sódio
/
Mutação de Sentido Incorreto
/
Caveolina 3
Tipo de estudo:
Risk_factors_studies
Idioma:
En
Revista:
Heart Rhythm
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Estados Unidos