Sudden infant death syndrome-associated mutations in the sodium channel beta subunits

BACKGROUND Approximately 10% of sudden infant death syndrome (SIDS) cases may stem from potentially lethal cardiac channelopathies, with approximately half of channelopathic SIDS involving the Na(V)1.5 cardiac sodium channel. Recently, Na-V beta subunits have been implicated in various cardiac arrhythmias. Thus, the 4 genes encoding NaV beta subunits represent plausible candidate genes for SIDS. OBJECTIVE This study sought to determine the spectrum, prevalence, and functional consequences of sodium channel beta-subunit mutations in a SIDS cohort. METHODS In this institutional review board-approved study, mutational analysis of the 4 beta-subunit genes, SCN1B to 4B, was performed using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing of DNA derived from 292 SIDS cases. Engineered mutations were coexpressed with SCN5A in HEK 293 cells and were whole-cell patch clamped. One of the putative SIDS-associated mutations was similarly studied in adenovirally transduced adult rat ventricular myocytes. RESULTS Three rare (absent in 200 to 800 reference alleles) missense mutations (beta 3-V36M, beta 3-V54G, and beta 4-S206L) were identified in 3 of 292 SIDS cases. Compared with SCN5A + beta 3-WT, beta 3-V36M significantly decreased peak I-Na and increased late I-Na, whereas beta 3-V54G resulted in a marked loss of function. beta 4-S206L accentuated late I-Na and positively shifted the midpoint of inactivation compared with SCN5A + beta 4-WT. In native cardiomyocytes, beta 4-S206L accentuated late I-Na and increased the ventricular action potential duration compared with beta 4-WT. CONCLUSION This study provides the first molecular and functional evidence to implicate the Na-V beta subunits in SIDS pathogenesis. Altered Na(V)1.5 sodium channel function due to beta-subunit mutations may account for the molecular pathogenic mechanism underlying approximately 1% of SIDS cases.