A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y
Leigh D. Plant, … , Rick A. Kittles, Steve A.N. Goldstein
Leigh D. Plant, … , Rick A. Kittles, Steve A.N. Goldstein
Published February 1, 2006
Citation Information: J Clin Invest. 2006;116(2):430-435. https://doi.org/10.1172/JCI25618.
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Research Article Cardiology

A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y

Abstract

Thousands die each year from sudden infant death syndrome (SIDS). Neither the cause nor basis for varied prevalence in different populations is understood. While 2 cases have been associated with mutations in type Vα, cardiac voltage-gated sodium channels (SCN5A), the “Back to Sleep” campaign has decreased SIDS prevalence, consistent with a role for environmental influences in disease pathogenesis. Here we studied SCN5A in African Americans. Three of 133 SIDS cases were homozygous for the variant S1103Y. Among controls, 120 of 1,056 were carriers of the heterozygous genotype, which was previously associated with increased risk for arrhythmia in adults. This suggests that infants with 2 copies of S1103Y have a 24-fold increased risk for SIDS. Variant Y1103 channels were found to operate normally under baseline conditions in vitro. As risk factors for SIDS include apnea and respiratory acidosis, Y1103 and wild-type channels were subjected to lowered intracellular pH. Only Y1103 channels gained abnormal function, demonstrating late reopenings suppressible by the drug mexiletine. The variant appeared to confer susceptibility to acidosis-induced arrhythmia, a gene-environment interaction. Overall, homozygous and rare heterozygous SCN5A missense variants were found in approximately 5% of cases. If our findings are replicated, prospective genetic testing of SIDS cases and screening with counseling for at-risk families warrant consideration.

Authors

Leigh D. Plant, Peter N. Bowers, Qianyong Liu, Thomas Morgan, Tingting Zhang, Matthew W. State, Weidong Chen, Rick A. Kittles, Steve A.N. Goldstein

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Figure 3

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Cells expressing Y1103 channels show sustained current at a low pHi. Who...
Cells expressing Y1103 channels show sustained current at a low pHi. Whole-cell currents were recorded in HEK-293 cells expressing S1103 or Y1103 channels as indicated with pipette and bath solutions (see Methods) with cells held at –100 mV and stepped to –30 mV for 100 ms at a rate of 0.5 Hz. Scale bars represent 300 pA and 20 ms. (A) Representative currents recorded from cells at the indicated pHi. (B) Ensemble averages of 500 sweeps recorded from 10 cells with the indicated channel and pHi. Late current was 5.23% ± 0.85% of peak (n = 10 cells). Peak currents were not significantly different and were –1311 ± 143 pA and 1252 ± 139 pA, for S1103 at normal and low pH, respectively, and 1267 ± 173 pA and 1195 ± 245 pA for Y1103 at normal and low pH, respectively (n = 10 cells per condition).