Department of Pharmacology, Medical School of Xi'an Jiaotong University.
Circ J. 2014;78(4):938-42. doi: 10.1253/circj.cj-13-0996. Epub 2014 Jan 31.
Loss-of-function mutations in the HCN4 gene have been shown to be associated with sinus dysfunction, but there are no reports on HCN4-mediated atrioventricular (AV) block. A novel missense HCN4 mutation G1097W was identified in a 69 year-old Japanese male with AV block, and we characterized the functional consequences of If-like channels reconstituted with the heterozygous HCN4 mutation.
Wild-type (WT) HCN4 or/and HCN4-G1097W were expressed in a heterologous cell expression system. A functional assay using a whole-cell patch-clamp demonstrated that the mutant If-like currents were activated at more negative voltages compared to WT currents, while they retained the sensitivity to changes in intracellular cyclic adenosine monophosphate (cAMP) levels. Co-expression of G1097W with WT channels showed dominant-negative effects, including a reduction in peak currents and a negative voltage shifting on reconstituted currents.
The HCN4-G1097W mutant channels displayed a loss-of-function type modulation on cardiac If channels and thus could predispose them to AV nodal dysfunction. These data provide a novel insight into the genetic basis for the AV block.
HCN4 基因的功能丧失性突变与窦房结功能障碍有关,但尚无关于 HCN4 介导的房室(AV)阻滞的报道。在一名 69 岁的日本男性 AV 阻滞患者中发现了一种新型错义 HCN4 突变 G1097W,我们对杂合 HCN4 突变 G1097W 重建的 If 样通道的功能后果进行了特征描述。
野生型(WT)HCN4 或/和 HCN4-G1097W 在异源细胞表达系统中表达。使用全细胞膜片钳的功能测定表明,与 WT 电流相比,突变的 If 样电流在更负的电压下被激活,而它们仍然对细胞内环磷酸腺苷(cAMP)水平的变化敏感。G1097W 与 WT 通道的共表达表现出显性负效应,包括峰值电流减少和重建电流的负电压移位。
HCN4-G1097W 突变通道对心脏 If 通道表现出功能丧失型调节,从而可能使它们易发生 AV 结功能障碍。这些数据为 AV 阻滞的遗传基础提供了新的见解。