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一种新的 HCN4 突变,G1097W,与房室传导阻滞有关。

A novel HCN4 mutation, G1097W, is associated with atrioventricular block.

机构信息

Department of Pharmacology, Medical School of Xi'an Jiaotong University.

出版信息

Circ J. 2014;78(4):938-42. doi: 10.1253/circj.cj-13-0996. Epub 2014 Jan 31.

Abstract

BACKGROUND

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.

METHODS AND RESULTS

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.

CONCLUSIONS

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.

摘要

背景

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。

方法和结果

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。

结论

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。

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