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 Na(V) 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 (beta3-V36M, beta3-V54G, and beta4-S206L) were identified in 3 of 292 SIDS cases. Compared with SCN5A+beta3-WT, beta3-V36M significantly decreased peak I(Na) and increased late I(Na), whereas beta3-V54G resulted in a marked loss of function. beta4-S206L accentuated late I(Na) and positively shifted the midpoint of inactivation compared with SCN5A+beta4-WT. In native cardiomyocytes, beta4-S206L accentuated late I(Na) and increased the ventricular action potential duration compared with beta4-WT.


CONCLUSIONS
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.
Tan
Bi-Hua
BH
Department of Medicine, Cardiovascular Section, University of Wisconsin, Madison, Wisconsin, USA.
Pundi
Kavitha N
KN
Van Norstrand
David W
DW
Valdivia
Carmen R
CR
Tester
David J
DJ
Medeiros-Domingo
Argelia
A
Makielski
Jonathan C
JC
Ackerman
Michael J
MJ
D000818:Animals; D001344:Autopsy; D053840:Brugada Syndrome / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D002102:Cadaver; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007223:Infant; D008133:Long QT Syndrome / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D008297:Male; D032383:Myocytes, Cardiac; D015995:Prevalence; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D012307:Risk Factors; D015222:Sodium Channels / Q000235:genetics*; D013398:Sudden Infant Death / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D017180:Tachycardia, Ventricular / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D014481:United States / Q000453:epidemiology; D062549:Voltage-Gated Sodium Channel beta-3 Subunit; D062585:Voltage-Gated Sodium Channel beta-4 Subunit
C493324:SCN3B protein, human; C477263:SCN4B protein, human; D015222:Sodium Channels; D062549:Voltage-Gated Sodium Channel beta-3 Subunit; D062585:Voltage-Gated Sodium Channel beta-4 Subunit