■Scn3b基因编码Navβ3,这是心肌细胞中快速钠通道的关键调节亚基。然而,在患有Brugada综合征(BrS)的中国人群中,其突变状态尚未得到表征,疾病病理的病理生理机制尚不明确。
■AScn3b(c.260C>T,在中国血统的BrS患者中鉴定出p.P87l)突变。功能分析表明,野生型的钠通道激活,突变样品,两者的共表达始于-55mv,并在-25mv达到峰值。突变组显着减少,大约60%,在-25mv的峰值钠通道激活电流(INa)中。当比较野生型时,半最大激活电压(V1/2)和斜率因子(k)的参数没有显着差异,突变体,和联合表达组(分别为P=0.98和P=0.65)。此外,稳态钠通道失活参数V1/2和k(P值分别为0.85和0.25)没有明显差异,野生型的激活时间常数τ(P=0.59)和晚期钠电流密度(P=0.23)也没有显著差异,突变体,和共同表达的群体。共聚焦成像和蛋白质印迹分析显示P871组中SCN3B和SCN5A的质膜定位降低。心脏动作电位的计算模拟表明,SCN3BP87l可以改变心内膜和心外膜内动作电位的形态,同时减少去极化的峰值。
■Scn3bP871突变的致病影响主要源自于峰值INa激活电流的降低以及Nav1.5和Navβ3的细胞表面表达的降低。这些改变可能会影响心脏动作电位配置,并导致BrS患者发生室性心律失常的风险。
UNASSIGNED: The Scn3b gene encodes for Navβ3, a pivotal regulatory subunit of the fast sodium channel in cardiomyocytes. However, its mutation status in the Chinese population suffering from Brugada Syndrome (BrS) has not been characterized, and the contributory pathophysiological mechanisms to disease pathology remain undefined.
UNASSIGNED: A Scn3b (c.260C>T, p.P87l) mutation was identified in a patient with BrS of Chinese descent. Functional analyses demonstrated that sodium channel activation for the wild type, mutant samples, and co-expression of both commenced at -55 mv and peaked at -25 mv. The mutant group exhibited a notable reduction, approximately 60%, in peak sodium channel activation current (INa) at -25 mv. The parameters for half-maximal activation voltages (V1/2) and slope factors (k) showed no significant differences when comparing wild type, mutant, and combined expression groups (P = 0.98 and P = 0.65, respectively). Additionally, no significant disparities were evident in terms of the steady-state sodium channel inactivation parameters V1/2 and k (with P-values of 0.85 and 0.25, respectively), nor were there significant differences in the activation time constant τ (P = 0.59) and late sodium current density (P = 0.23) across the wild-type, mutant, and co-expressed groups. Confocal imaging and Western blot analysis demonstrated decreased plasma membrane localization of SCN3B and SCN5A in the P87l group. Computational simulations of cardiac action potentials suggested that SCN3B P87l can alter the morphology of the action potentials within the endocardium and epicardium while reducing the peak of depolarization.
UNASSIGNED: The pathogenic impact of the Scn3b P87l mutation predominantly originates from a reduction in peak INa activation current coupled with decreased cell surface expression of Nav1.5 and Navβ3. These alterations may influence cardiac action potential configurations and contribute to the risk of ventricular arrhythmias in individuals with BrS.