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 4

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Single Y1103 channels show abnormal late reopenings. Single channels stu...
Single Y1103 channels show abnormal late reopenings. Single channels studied in inside-out, off-cell patches excised from HEK-293 cells. Currents were stimulated every 2.5 seconds by a 50-ms depolarizing pulse to –30 mV from a holding potential of –120 mV. Data were recorded at filter and sampling frequencies of 5 and 50 kHz, respectively. Pipettes were filled with bath solution described in Methods. Cells were perfused with the pipette solution described in Methods. For each cell, null sweeps (with no channel activity) were identified, averaged offline, and subtracted from data sweeps before analysis. For display purposes, data were refiltered offline using a 2-kHz Bessel filter. (A) With depolarization, single S1103 channels opened, inactivated rapidly, and did not reopen. This behavior was unaltered when internal pH was lowered from 7.4 to 6.7. Null traces at pH 7.4 and 6.7 were 50% ± 2.7% (n = 15 patches, 1,367 sweeps) and 51% ± 3.4% (n = 12 patches, 1,028 sweeps), respectively. In contrast, Y1103 channels behaved like S1103 channels at pH 7.4 but showed late reopenings at pH 6.7. Null traces were 51% ± 4.5% at pH 7.4 (n = 8 patches, 742 sweeps) and 51.7 ± 2.5% (n = 10 patches, 942 sweeps) when pH was reduced to 6.7. (B) Ensemble average traces (n = 100–150 sweeps) for the indicated channels and conditions. Y1103 channels failed to remain in the inactivated state when exposed to internal pH 6.7. Scale bars: 0.5 pA; 10 ms.