AbstractAbstract session 32: Pediatric/adult congenital heart disease II: Fetal arrhythmias, genetic basis for arrhythmias, AFAB32-3: Identification of CAV3-encoded caveolin-3 mutations in sudden infant death syndrome
Section snippets
Background
Sudden infant death syndrome (SIDS) is one of the leading causes of death in the United States during the first year of life. Pathogenic mechanisms for the majority of SIDS remain elusive. Long QT syndrome (LQTS)-associated cardiac channel mutations may be responsible for approximately 10% of SIDS. Recently, we established CAV3 as a novel LQTS-associated gene with mutations in the CAV3-encoded caveolin-3 producing a gain-of-function, LQT3-like molecular/cellular phenotype. Here, we considered
Methods
Using polymerase chain reaction, denaturing high performance liquid chromatography, and direct DNA sequencing, postmortem genetic testing of CAV3 was performed on genomic DNA isolated from frozen necropsy tissue on 135 unrelated cases of SIDS (57 females, 84 white, 50 black, 1 Hispanic, average age = 3 months) who were referred to Mayo Clinic’s Sudden Death Genomics Laboratory for molecular autopsy. CAV3 mutations were engineered using site-directed mutagenesis and heterologously expressed in
Results
Overall, distinct CAV3 missense mutations (V14L, T78M, and L79R) were identified in 3/50 black infants (2 females, ages 2 months, 6 months, and 8 months). No mutations were detected among the 84 white infants. T78M was published previously as a LQTS-associated mutation. All three amino acid substitutions involved highly conserved residues and were absent in 400 reference alleles. T78M and L79R localize to the intra-membrane domain of caveolin-3. The functional effect of all 3 missense mutations
Conclusions
This large molecular autopsy series of SIDS provides the first molecular and functional evidence to implicate CAV3 as a novel candidate gene in the pathogenesis of SIDS. Akin to our sentinel report of CAV3-LQTS, these SIDS-associated caveolin-3 mutations functionally disrupt otherwise normal cardiac sodium channels.