Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Via Pier Lombardo, 22, 20135 Milan, Italy.
Istituto Auxologico Italiano, IRCCS, Laboratory of Cardiovascular Genetics, via Zucchi 18, 20095 Cusano Milanino, MI, Italy.
Eur Heart J. 2021 Dec 7;42(46):4743-4755. doi: 10.1093/eurheartj/ehab582.
Mutation type, location, dominant-negative IKs reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent IKs stimulation via protein kinase A (PKA) influence the clinical severity of long QT syndrome type 1 (LQT1). Given the malignancy of KCNQ1-p.A341V, we assessed whether mutations neighbouring p.A341V in the S6 channel segment could also increase arrhythmic risk.
Clinical and genetic data were obtained from 1316 LQT1 patients [450 families, 166 unique KCNQ1 mutations, including 277 p.A341V-positive subjects, 139 patients with p.A341-neighbouring mutations (91 missense, 48 non-missense), and 900 other LQT1 subjects]. A first cardiac event represented the primary endpoint. S6 segment missense variant characteristics, particularly cAMP stimulation responses, were analysed by cellular electrophysiology. p.A341-neighbouring mutation carriers had a QTc shorter than p.A341V carriers (477 ± 33 vs. 490 ± 44 ms) but longer than the remaining LQT1 patient population (467 ± 41 ms) (P < 0.05 for both). Similarly, the frequency of symptomatic subjects in the p.A341-neighbouring subgroup was intermediate between the other two groups (43% vs. 73% vs. 20%; P < 0.001). These differences in clinical severity can be explained, for p.A341V vs. p.A341-neighbouring mutations, by the p.A341V-specific impairment of IKs regulation. The differences between the p.A341-neighbouring subgroup and the rest of LQT1 mutations may be explained by the functional importance of the S6 segment for channel activation.
KCNQ1 S6 segment mutations surrounding p.A341 increase arrhythmic risk. p.A341V-specific loss of PKA-dependent IKs enhancement correlates with its phenotypic severity. Cellular studies providing further insights into IKs-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management.
突变类型、位置、IKs 的显性负性减少以及通过蛋白激酶 A (PKA) 可能导致的环磷酸腺苷 (cAMP) 依赖性 IKs 刺激丧失,都会影响 1 型长 QT 综合征 (LQT1) 的临床严重程度。鉴于 KCNQ1-p.A341V 的恶性程度,我们评估了 S6 通道节段中 p.A341V 附近的突变是否也会增加心律失常风险。
从 1316 例 LQT1 患者[450 个家系,166 个独特的 KCNQ1 突变,包括 277 例 p.A341V 阳性患者,139 例 p.A341 邻近突变(91 个错义突变,48 个非错义突变)和 900 例其他 LQT1 患者]获得临床和遗传数据。首次心脏事件为主要终点。通过细胞电生理学分析 S6 节段错义变异特征,特别是 cAMP 刺激反应。p.A341 邻近突变携带者的 QTc 短于 p.A341V 携带者(477±33 比 490±44 ms),但长于其余 LQT1 患者群体(467±41 ms)(两者均 P<0.05)。同样,p.A341 邻近亚组中症状性患者的频率也介于其他两组之间(43%比 73%比 20%;P<0.001)。对于 p.A341V 与 p.A341 邻近突变,这种临床严重程度的差异可以通过 IKs 调节的 p.A341V 特异性损害来解释。p.A341 邻近亚组与其余 LQT1 突变之间的差异可能是由于 S6 节段对通道激活的功能重要性。
KCNQ1 S6 节段突变围绕 p.A341 增加心律失常风险。p.A341V 特异性 PKA 依赖性 IKs 增强丧失与其表型严重程度相关。细胞研究为 IKs 通道调节提供了进一步的见解,并了解了结构-功能关系,这可能会改善风险分层。这些发现对临床管理有影响。