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

Department of Medicine, Cardiovascular Section, University of Wisconsin, Madison, Wisconsin, USA.
Heart rhythm: the official journal of the Heart Rhythm Society (Impact Factor: 5.08). 02/2010; 7(6):771-8. DOI: 10.1016/j.hrthm.2010.01.032
Source: PubMed


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.
This study sought to determine the spectrum, prevalence, and functional consequences of sodium channel beta-subunit mutations in a SIDS cohort.
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.
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.
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.

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Available from: Michael John Ackerman, Feb 14, 2014
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    • "About 28% of the children with an unexplained SCD (between 1 and 18 years, mean age: 12.3 ± 3.8 years) were carriers of mutations in LQTS causal genes (97). In SIDS, mutations in SCN5A seemed predominant (98, 99), but, mutations in KCNQ1, KCNH2, KCNE2, and CAV3, SCN4B, and SCN3B were also found (100, 101). Intrauterine fetal deaths were also reported due to defects in cardiac ion channel genes (12, 102). "
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    ABSTRACT: Primary cardiac arrhythmias are often caused by defects, predominantly in the genes responsible for generation of cardiac electrical potential, i.e., cardiac rhythm generation. Due to the variability in underlying genetic defects, type, and location of the mutations and putative modifiers, clinical phenotypes could be moderate to severe, even absent in many individuals. Clinical presentation and severity could be quite variable, syncope, or sudden cardiac death could also be the first and the only manifestation in a patient who had previously no symptoms at all. Despite usual familial occurrence of such cardiac arrhythmias, disease causal genetic defects could also be de novo in significant number of patients. Long QT syndrome (LQTS) is the most eloquently investigated primary cardiac rhythm disorder. A genetic defect can be identified in ∼70% of definitive LQTS patients, followed by Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) and Brugada syndrome (BrS), where a genetic defect is found in <40% cases. In addition to these widely investigated hereditary arrhythmia syndromes, there remain many other relatively less common arrhythmia syndromes, where researchers also have unraveled the genetic etiology, e.g., short QT syndrome (SQTS), sick sinus syndrome (SSS), cardiac conduction defect (CCD), idiopathic ventricular fibrillation (IVF), early repolarization syndrome (ERS). There exist also various other ill-defined primary cardiac rhythm disorders with strong genetic and familial predisposition. In the present review we will focus on the genetic basis of LQTS and its clinical management. We will also discuss the presently available genetic insight in this context from Saudi Arabia.
    Frontiers in Pediatrics 11/2013; 1:39. DOI:10.3389/fped.2013.00039
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    • "Functionally relevant mutations in cardiac ion channel genes that commonly cause LQTS (such as KCNQ1, KCNH2, and SCN5A) have been identified in up to 10% of SIDS cases [9] [22] [23]. Mutations in genes associated with BrS (KCND3, SCN1Bb) [24] [25] and CPVT (RyR2) [26] have been identified in a smaller subset of SIDS, supporting the role of cardiac channelopathies in predisposing to sudden death in SIDS. "
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    • "Mutations in all four b-subunits have been linked to cardiac pathologies including Brugada syndrome (b1 and b3), atrial fibrillation (b1, b2 and b3), ventricular fibrillation (b3) and long QT syndrome (b4) (Table 1). Mutations in b3 and b4 have also been linked to sudden infant death syndrome (found in 1% of cases) due to reduced peak sodium current through Na V 1.5 and enhanced 'late sodium current' (Tan et al., 2010). Expression levels of VGSC b-subunits vary in different pathological conditions (nerve injury, pain, Huntington's disease) and knockout models of VGSC b-subunits display pain, epilepsy and ataxia phenotypes (Patino and Isom, 2010), suggesting that the range of VGSC b-subunit roles in pathological conditions may be wider than known. "
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