Department of Physiology and Pharmacology, University of Western Ontario, London, ON, N6A 5C1 Canada.
Int J Mol Sci. 2018 Mar 25;19(4):977. doi: 10.3390/ijms19040977.
Atrial fibrillation (AF) is the most common form of cardiac arrhythmia. Recently, four novel heterozygous Cx40 mutations-K107R, L223M, Q236H, and I257L-were identified in 4 of 310 unrelated AF patients and a followup genetic analysis of the mutant carriers' families showed that the mutants were present in all the affected members. To study possible alterations associated with these Cx40 mutants, including their cellular localization and gap junction (GJ) function, we expressed GFP-tagged and untagged mutants in connexin-deficient model cells. All four Cx40 mutants showed clustered localization at cell-cell junctions similar to that observed of wildtype Cx40. However, cell pairs expressing Cx40 Q236H, but not the other individual mutants, displayed a significantly lower GJ coupling conductance (G) than wildtype Cx40. Similarly, co-expression of Cx40 Q236H with Cx43 resulted in a significantly lower G. Transjunctional voltage-dependent gating (V gating) properties were also altered in the GJs formed by Q236H. Reduced GJ function and altered V gating may play a role in promoting the Q236H carriers to AF.
心房颤动（AF）是最常见的心律失常形式。最近，在 310 名无关的 AF 患者中发现了 4 种新型杂合 Cx40 突变-K107R、L223M、Q236H 和 I257L-，对突变携带者家族的后续遗传分析表明，这些突变存在于所有受影响的成员中。为了研究与这些 Cx40 突变相关的可能改变，包括它们的细胞定位和间隙连接（GJ）功能，我们在连接蛋白缺陷型模型细胞中表达了 GFP 标记的和未标记的突变体。所有四种 Cx40 突变体在细胞-细胞连接处均表现出与野生型 Cx40 相似的聚集定位。然而，表达 Cx40 Q236H 的细胞对，而不是其他单个突变体，显示出明显低于野生型 Cx40 的 GJ 偶联传导（G）。同样，Cx40 Q236H 与 Cx43 的共表达也导致 G 明显降低。由 Q236H 形成的 GJ 中的跨连接电压依赖性门控（V 门控）特性也发生了改变。GJ 功能降低和 V 门控改变可能在促进 Q236H 携带者发生 AF 中起作用。
