Masonic Medical Research Laboratory, Utica, NY, USA.
Heart Rhythm. 2012 May;9(5):760-9. doi: 10.1016/j.hrthm.2011.12.006. Epub 2011 Dec 7.
Cardiac sodium channel β-subunit mutations have been associated with several inherited cardiac arrhythmia syndromes.
To identify and characterize variations in SCN1Bb associated with Brugada syndrome (BrS) and sudden infant death syndrome (SIDS).
All known exons and intron borders of the BrS-susceptibility genes were amplified and sequenced in both directions. Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using co-immunoprecipitation and whole-cell patch-clamp techniques.
Patient 1 was a 44-year-old man with an ajmaline-induced type 1 ST-segment elevation in V1 and V2 supporting the diagnosis of BrS. Patient 2 was a 62-year-old woman displaying a coved-type BrS electrocardiogram who developed cardiac arrest during fever. Patient 3 was a 4-month-old female SIDS case. A R214Q variant was detected in exon 3A of SCN1Bb (Na(v)1B) in all three probands, but not in any other gene previously associated with BrS or SIDS. R214Q was identified in 4 of 807 ethnically-matched healthy controls (0.50%). Co-expression of SCN5A/WT + SCN1Bb/R214Q resulted in peak sodium channel current (I(Na)) 56.5% smaller compared to SCN5A/WT + SCN1Bb/WT (n = 11-12, P<0.05). Co-expression of KCND3/WT + SCN1Bb/R214Q induced a Kv4.3 current (transient outward potassium current, I(to)) 70.6% greater compared with KCND3/WT + SCN1Bb/WT (n = 10-11, P<0.01). Co-immunoprecipitation indicated structural association between Na(v)β1B and Na(v)1.5 and K(v)4.3.
Our results suggest that R214Q variation in SCN1Bb is a functional polymorphism that may serve as a modifier of the substrate responsible for BrS or SIDS phenotypes via a combined loss of function of sodium channel current and gain of function of transient outward potassium current.
心脏钠离子通道 β 亚基的突变与多种遗传性心律失常综合征有关。
鉴定并描述与 Brugada 综合征（BrS）和婴儿猝死综合征（SIDS）相关的 SCN1Bb 变异。
扩增 BrS 易感性基因的所有已知外显子和内含子边界，并进行双向测序。野生型（WT）和突变基因在 TSA201 细胞中表达，并使用共免疫沉淀和全细胞膜片钳技术进行研究。
患者 1 为 44 岁男性，服用阿马林后 V1 和 V2 导联出现 1 型 ST 段抬高，支持 BrS 诊断。患者 2 为 62 岁女性，心电图呈穹窿型 BrS，发热时发生心脏骤停。患者 3 为 4 月龄 SIDS 病例。在所有 3 名先证者的 SCN1Bb（Na（v）1B）第 3A 外显子中均检测到 R214Q 变异，但在以前与 BrS 或 SIDS 相关的其他基因中未检测到。在 807 名种族匹配的健康对照者中，有 4 名（0.50%）检测到 R214Q。与 SCN5A/WT+SCN1Bb/WT 相比，SCN5A/WT+SCN1Bb/R214Q 的峰值钠电流（I（Na））小 56.5%（n=11-12，P<0.05）。与 KCND3/WT+SCN1Bb/WT 相比，KCND3/WT+SCN1Bb/R214Q 诱导的 Kv4.3 电流（瞬时外向钾电流，I（to））大 70.6%（n=10-11，P<0.01）。共免疫沉淀表明 Na（v）β1B 和 Na（v）1.5 与 K（v）4.3 之间存在结构关联。
我们的结果表明，SCN1Bb 中的 R214Q 变异是一种功能性多态性，可能通过钠离子通道电流功能丧失和瞬时外向钾电流功能获得，作为 BrS 或 SIDS 表型的相关底物的修饰因子。
