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 5

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Abnormal reopenings are suppressed by mexiletine. Single channels were s...
Abnormal reopenings are suppressed by mexiletine. Single channels were studied in inside-out, off-cell patches as in Figure 3. (A) Dose-response curves for phasic block by mexiletine of peak macroscopic currents with S1103 (open squares) and Y1103 (filled squares) channels studied in whole-cell mode. Each point shows the average percent reduction in peak current by the dose indicated after a series of repetitive depolarizing stimuli (n = 3–7 cells). Cells were depolarized to –30 mV from a holding potential of –100 mV for 10 ms at 2.5 Hz to mimic a rate of 150 bpm. Inset: Representative S1103 current traces evoked by a pulse in drug-free solution (control) and the first (pulse 1) to show tonic block and fiftieth (pulse 50) to show phasic block by 10 μM mexiletine (mex). Values for tonic and phasic block by mexiletine, propranolol, and amiodarone are reported in Supplemental Table 4. (B) Single Y1103 channels studied in inside-out off-cell patches showed that late reopenings of variant channels were fully suppressed by 5 μM mexiletine. Null traces in the absence of drug (see Figure 3B) at pH 7.4 and 6.7 were 51% ± 4.5% (n = 8 patches, 742 sweeps) and 52 ± 2.5% (n = 10 patches, 942 sweeps), respectively; null traces at pH 6.7 with drug were 55% ± 3.5% (n = 6 patches, 561 sweeps). The therapeutic blood level of mexiletine is 0.8–2.0 μg/ml (3.7–9.3 μM). Scale bars: 2 ms, 200 pA (A); 0.3 pA, 10 ms (B).