A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y
A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y
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DOI：
10.1172/jci25618
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发表时间：
2006-02-01
影响因子：
15.9
通讯作者：
Goldstein, SAN
中科院分区：
文献类型：
--
作者：
Plant, LD;Bowers, PN;Goldstein, SAN
每年有数千人死于婴儿猝死综合症。不同人群患病率差异的原因和基础尚不清楚。虽然有2例病例与心脏电压门控钠通道（SCN5A） V α型突变有关，但“恢复睡眠”运动降低了SIDS的患病率，这与环境影响在疾病发病机制中的作用是一致的。在这里我们研究了非裔美国人的SCN5A。133例小岛屿发展中国家中有3例是变异S1103Y的纯合子。在对照组中，1056人中有120人携带杂合基因型，这种基因型先前与成人心律失常风险增加有关。这表明携带2个S1103Y基因拷贝的婴儿患SIDS的风险增加24倍。发现变异Y1103通道在体外基线条件下正常运作。由于SIDS的危险因素包括呼吸暂停和呼吸性酸中毒，Y1103和野生型通道受到细胞内ph值降低的影响。只有Y1103通道出现功能异常，表现出药物美西汀抑制的迟发性重新开放。这种变异似乎赋予了酸中毒诱发心律失常的易感性，这是一种基因与环境的相互作用。总体而言，在大约5%的病例中发现了纯合子和罕见的杂合子SCN5A错义变异。如果我们的发现被重复，对小岛屿发展中国家病例的前瞻性基因检测和对高危家庭的筛查咨询是值得考虑的。
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 V alpha, 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.