Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients.
Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients.
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DOI：
10.1080/19336950.2018.1475794
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Tan BH
中科院分区：
文献类型：
--
作者：
Hu RM;Tester DJ;Li R;Sun T;Peterson BZ;Ackerman MJ;Makielski JC;Tan BH
简介：编码SCN 5A的心脏钠通道α亚基的个体突变通常导致单一心律失常疾病，一些导致混合生物物理或临床表型。在这里，我们报告了一个婴儿，女性患者窝藏在SCN 5A的N406 K突变与一个显着的和混合的生物物理表型，并评估致病机制。方法和结果：1例患者在睡眠中反复发作，并伴有尖端扭转型室性心动过速，QTc为530 ms。突变分析鉴定了SCN 5A中的N406 K突变。通过定点诱变对突变进行工程改造，并在HEK 293细胞中异源表达。在与和不与美西律孵育48小时后，用标准全细胞膜片钳技术测量宏观电压门控钠电流（INa）。与宽型（WT）通道相比，SCN 5A-N406 K引起显著降低的峰值INa和显著增加的晚期INa。此外，美西律还能恢复突变型通道降低的峰值INa，并抑制突变型通道升高的晚期INa。结论：SCN 5A-N406 K通道在晚期INa中显示“功能获得”和在峰值INa密度中显示“功能丧失”，从而导致混合生物物理表型。此外，我们的发现可能提供了第一个例子，即mexileprazole发挥双重拯救的“功能获得”和“功能丧失”的突变钠通道。
Introduction: Individual mutations in the SCN5A-encoding cardiac sodium channel α-subunit usually cause a single cardiac arrhythmia disorder, some cause mixed biophysical or clinical phenotypes. Here we report an infant, female patient harboring a N406K mutation in SCN5A with a marked and mixed biophysical phenotype and assess pathogenic mechanisms. Methods and Results: A patient suffered from recurrent seizures during sleep and torsades de pointes with a QTc of 530 ms. Mutational analysis identified a N406K mutation in SCN5A. The mutation was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells. After 48 hours incubation with and without mexiletine, macroscopic voltage-gated sodium current (INa) was measured with standard whole-cell patch clamp techniques. SCN5A-N406K elicited both a significantly decreased peak INa and a significantly increased late INa compared to wide-type (WT) channels. Furthermore, mexiletine both restored the decreased peak INa of the mutant channel and inhibited the increased late INa of the mutant channel. Conclusion: SCN5A-N406K channel displays both “gain-of-function” in late INa and “loss-of-function” in peak INa density contributing to a mixed biophysical phenotype. Moreover, our finding may provide the first example that mexiletine exerts a dual rescue of both “gain-of-function” and “loss-of-function” of the mutant sodium channel.
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影响因子：
3.7
作者：
Hu RM;Tan BH;Tester DJ;Song C;He Y;Dovat S;Peterson BZ;Ackerman MJ;Makielski JC
通讯作者：
Makielski JC
DOI：
10.1111/j.1540-8167.2005.50104.x
发表时间：
2005-09-01
影响因子：
2.7
作者：
Grant, AO
通讯作者：
Grant, AO
影响因子：
37.8
作者：
Kapa S;Tester DJ;Salisbury BA;Harris-Kerr C;Pungliya MS;Alders M;Wilde AA;Ackerman MJ
通讯作者：
Ackerman MJ
DOI：
10.1161/circgenetics.111.960633
发表时间：
2011-10
期刊：
Circulation. Cardiovascular genetics
影响因子：
--
作者：
Shinlapawittayatorn K;Dudash LA;Du XX;Heller L;Poelzing S;Ficker E;Deschênes I
通讯作者：
Deschênes I
DOI：
10.1038/nrcardio.2014.85
发表时间：
2014-10
期刊：
Nature reviews. Cardiology
影响因子：
--
作者：
Liu M;Yang KC;Dudley SC Jr
通讯作者：
Dudley SC Jr