A mutant HCN4 channel in a family with bradycardia, left bundle branch block, and left ventricular noncompaction
A mutant HCN4 channel in a family with bradycardia, left bundle branch block, and left ventricular noncompaction
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DOI：
10.1007/s00380-018-1116-6
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发表时间：
2018-01
影响因子：
1.5
通讯作者：
Ryosuke Yokoyama;Koshi Kinoshita;Yukiko Hata;Masayoshi Abe;Kenta Matsuoka;Keiichi Hirono;M. Kano;M. Nakazawa;F. Ichida;Naoki Nishida;T. Tabata
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文献类型：
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作者：
Ryosuke Yokoyama;Koshi Kinoshita;Yukiko Hata;Masayoshi Abe;Kenta Matsuoka;Keiichi Hirono;M. Kano;M. Nakazawa;F. Ichida;Naoki Nishida;T. Tabata
我们发现一名表现为左束支传导阻滞和左心室致密化不全的女婴携带未调查的基因突变：HCN4(G811E)、SCN5A(L1988R)、DMD(S2384Y)和EMD(R203H)。在这里，我们探讨了HCN4(G811E)可能的致病性，它导致超极化激活的环核苷酸门控通道4(心脏起搏器通道的主要亚单位)中的G811E替换。在HEK293T细胞异源表达系统中的电压钳测量表明，HCN4(G811E)略微降低了全细胞HCN4通道电导，但不影响门控动力学、单位电导或cAMP依赖的电压依赖性调节。免疫细胞化学和免疫印迹分析表明，G811E突变不损害异源表达系统中通道亚单位的膜转运。提示HCN4(G811E)可能不是引起心脏疾病的单基因因子。
We found that a female infant presenting with left bundle branch block and left ventricular noncompaction carries uninvestigated gene mutations HCN4(G811E), SCN5A(L1988R), DMD(S2384Y), and EMD(R203H). Here, we explored the possible pathogenicity of HCN4(G811E), which results in a G811E substitution in hyperpolarization-activated cyclic nucleotide-gated channel 4, the main subunit of the cardiac pacemaker channel. Voltage-clamp measurements in a heterologous expression system of HEK293T cells showed that HCN4(G811E) slightly reduced whole-cell HCN4 channel conductance, whereas it did not affect the gating kinetics, unitary conductance, or cAMP-dependent modulation of voltage-dependence. Immunocytochemistry and immunoblot analysis showed that the G811E mutation did not impair the membrane trafficking of the channel subunit in the heterologous expression system. These findings indicate that HCN4(G811E) may not be a monogenic factor to cause the cardiac disorders.