The common African American polymorphism SCN5A-S1103Y interacts with mutation SCN5A-R680H to increase late Na current
The common African American polymorphism SCN5A-S1103Y interacts with mutation SCN5A-R680H to increase late Na current
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DOI：
10.1152/physiolgenomics.00198.2010
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发表时间：
2011-05-01
影响因子：
4.6
通讯作者：
Makielski, Jonathan C.
中科院分区：
文献类型：
--
作者：
Cheng, Jianding;Tester, David J.;Makielski, Jonathan C.
Cheng J，Tester DJ，Tan BH，Valdivia CR，Kroboth S，Ye B，January CT，阿克曼MJ，Makielski JC.常见的非洲裔美国人多态性SCN 5A-S1103 Y与突变SCN 5A-R680 H相互作用以增加晚期Na电流。Physiol Genomics 43：461-466，2011.首次发表于2011年3月8日; doi：10.1152/physiolgenomics.00198.2010.-常见的SCN 5A-S1103 Y多态性（与非裔美国人13%的等位基因频率相似）是心律失常、不明原因猝死（SUD）和婴儿猝死综合征的危险因素。在一名23岁的非洲裔美国男子在踢足球时昏倒的尸检阴性SUD病例中，我们假设S1103 Y与其他SCN 5A变体相互作用，以病理性改变钠电流（I（Na））。对受害者的疟疾相关基因的突变分析显示了SCN 5A-R680 H和SCN 5A-S1103 Y的变体。这些变体分别制备并在选择性剪接变体背景（SCN 5A-Q1077 del和Q1077）的相同cDNA构建体中制备，并在HEK 293细胞中表达。在最丰富的SCN 5A-Q1077 del中，单独S1103 Y的晚期I（Na）与野生型（WT）没有显著差异。然而，与WT相比，R680 H、R680 H + S1103 Y（共表达）和R680 H/S1103 Y（在相同cDNA上）的晚期I（Na）分别增加了2.1倍、3.4倍和3.6倍。细胞内酸中毒（pH 6.7）使S1103 Y、R680 H、R680 H + S1103 Y和R680 H/S1103 Y的晚期I（Na）分别增加2.2、2.4、5.0和5.5倍（与pH 6.7时的WT相比）。在丰度较低的SCN 5A-Q1077中的表达显示晚期I（Na）没有增加。这是一个共同的多态性S1103 Y与另一个突变的主要转录本Q1077 del的SCN 5A的功能相互作用的初步报告。本例可能是酸中毒的“双重打击”和环境因素共同作用而导致中毒性猝死。
Cheng J, Tester DJ, Tan BH, Valdivia CR, Kroboth S, Ye B, January CT, Ackerman MJ, Makielski JC. The common African American polymorphism SCN5A-S1103Y interacts with mutation SCN5A-R680H to increase late Na current. Physiol Genomics 43: 461-466, 2011. First published March 8, 2011; doi: 10.1152/physiolgenomics.00198.2010.-The common polymorphism SCN5A-S1103Y (similar to 13% allelic frequency in African Americans) is a risk factor for arrhythmia, sudden unexplained death (SUD), and sudden infant death syndrome. Prompted by a case of autopsy-negative SUD in a 23-year-old African American man who collapsed while playing football, we hypothesized that S1103Y interacted with other SCN5A variants to pathologically modify sodium current (I(Na)). Mutational analysis of arrhythmia-associated genes in the victim revealed the variants SCN5A-R680H and SCN5A-S1103Y. These variants were made both separately and in the same cDNA construct of the alternative splice variant backgrounds (SCN5A-Q1077del and Q1077) and expressed in HEK293 cells. In the most abundant SCN5A-Q1077del, late I(Na) for S1103Y alone was not significantly different from wild type (WT). However, late I(Na) for R680H, R680H+S1103Y (coexpressed), and R680H/S1103Y (on the same cDNA) was increased 2.1-, 3.4-, and 3.6-fold, respectively, compared with WT. Intracellular acidosis (pH 6.7) increased late I(Na) for S1103Y, R680H, R680H + S1103Y, and R680H/S1103Y by 2.2-, 2.4-, 5.0-, and 5.5-fold, respectively, compared with WT at pH 6.7. Expression in the less abundant SCN5A-Q1077 showed no increased late I(Na). This is the initial report of a functional interaction for the common polymorphism S1103Y with another mutation in the major transcript Q1077del of SCN5A. The "double hit" and environmental factor of acidosis may have converged to cause arrhythmic sudden death in this case.