Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation
Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation
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DOI：
10.1172/jci200215570
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发表时间：
2002-10-01
影响因子：
15.9
通讯作者：
Priori, S
中科院分区：
文献类型：
--
作者：
Grant, AO;Carboni, MP;Priori, S
心脏Na+通道53-残基III/IV结构域间连接体中的12个正电荷的功能尚不清楚。我们已经确定了一个四代家族，包括17个基因携带者，他们患有长QT综合征、Brugada综合征和传导系统疾病，并在连接体中缺失赖氨酸1500 （DeltaK1500）。三名家庭成员突然死亡。我们通过测量表达野生型和DeltaK1500突变通道的293-EBNA细胞的全细胞和单通道电流，研究了这种突变的功能后果。突变将一半失活电位(V（1/2)b（无穷））移至更负的值，并降低了与失活价1的降低一致的电压依赖性。失活的转变是闭合状态失活率增加的结果（在-100 mV时增加了11倍）。在DeltaK1500突变体中，半激活电位（V(1/2)m）转移到更正的电位，其电压依赖性降低了50%。为了确定正电荷缺失是否是门控变化的基础，我们进行了突变K1500Q和K1500E （δ电荷，-1,-2）。对于这两种突变，V(1/2)h（无穷大）都向控制方向移动；然而，V(1/2)m逐渐转向更正的电位。DeltaK1500突变体通道中Na+电流后期分量增加。这些变化可以解释该亲缘的复杂表型，并指出III/IV连接体在通道激活中的重要作用。
The function of the 12 positive charges in the 53-residue III/IV interdomain linker of the cardiac Na+ channel is unclear. We have identified a four-generation family, including 17 gene carriers with long QT syndrome, Brugada syndrome, and conduction system disease with deletion of lysine 1500 (DeltaK1500) within the linker. Three family members died suddenly. We have examined the functional consequences of this mutation by measuring whole-cell and single-channel currents in 293-EBNA cells expressing the wild-type and DeltaK1500 mutant channel. The mutation shifted the potential for half inactivation (V(1/2)b(infinity)) to more negative values and reduced its voltage dependence consistent with a reduction of inactivation valence of 1. The shift in inactivation was the result of an increase in closed-state inactivation rate (11-fold at -100 mV). The potential for half activation (V(1/2)m) was shifted to more positive potentials, and its voltage dependence reduced by 50% in the DeltaK1500 mutant. To determine whether the positive charge deletion was the basis for the gating changes, we performed the mutations K1500Q and K1500E (Delta charge, -1, -2). For both mutations, V(1/2)h(infinity) was shifted back toward control; however, V(1/2)m, shifted progressively to more positive potentials. The late component of Na+ current was increased in the DeltaK1500 mutant channel. These changes can account for the complex phenotype in this kindred and point to an important role of the III/IV linker in channel activation.