Plant Leigh D, Bowers Peter N, Liu Qianyong, Morgan Thomas, Zhang Tingting, State Matthew W, Chen Weidong, Kittles Rick A, Goldstein Steve A N
Department of Pediatrics and Institute for Molecular Pediatric Sciences, Pritzker School of Medicine, Biological Sciences Division, University of Chicago, Chicago, Illinois 60637, USA.
J Clin Invest. 2006 Feb;116(2):430-5. doi: 10.1172/JCI25618.
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 Valpha, 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.
每年有数千名婴儿死于婴儿猝死综合征（SIDS）。目前尚不清楚不同人群中该病发病率各异的原因和基础。虽然已有2例病例与心脏电压门控钠通道（SCN5A）的α型Valpha突变有关，但“仰睡运动”已降低了SIDS的发病率，这与环境影响在疾病发病机制中的作用相一致。在此，我们对非裔美国人中的SCN5A进行了研究。在133例SIDS病例中，有3例为变异型S1103Y的纯合子。在对照组中，1056人中有120人为杂合基因型携带者，该基因型先前与成人心律失常风险增加有关。这表明携带两份S1103Y拷贝的婴儿患SIDS的风险增加了24倍。研究发现，变异型Y1103通道在体外基线条件下功能正常。由于SIDS的风险因素包括呼吸暂停和呼吸性酸中毒，因此对Y1103通道和野生型通道进行了细胞内pH降低的处理。只有Y1103通道获得了异常功能，表现出可被美西律抑制的延迟重新开放。该变异似乎赋予了对酸中毒诱导的心律失常的易感性，这是一种基因-环境相互作用。总体而言，在约5%的病例中发现了纯合和罕见的杂合SCN5A错义变异。如果我们的研究结果得到重复验证，那么对SIDS病例进行前瞻性基因检测以及对高危家庭进行咨询筛查值得考虑。
