错义突变
先证者
导航1
钠通道
导航1.5
周期性麻痹
门控
突变
高钾血症
病变
医学
生物
内科学
内分泌学
麻痹
遗传学
神经科学
化学
病理
基因
钠
外科
有机化学
作者
Kazuki Segawa,Masahiro Nishiyama,Itsuki Mori,Tomoya Kubota,Masanori Takahashi
标识
DOI:10.1016/j.braindev.2022.12.003
摘要
Hyperkalemic periodic paralysis (HyperPP) is an autosomal dominantly inherited disease characterized by episodic paralytic attacks with hyperkalemia, and is caused by mutations of the SCN4A gene encoding the skeletal muscle type voltage-gated sodium channel Nav1.4. The pathological mechanism of HyperPP was suggested to be associated with gain-of-function changes for Nav1.4 gating, some of which are defects of slow inactivation.We identified a HyperPP family consisting of the proband and his mother, who showed a novel heterozygous SCN4A variant, p.V792G, in an inner pore lesion of segment 6 in Domain II of Nav1.4. Clinical and neurophysiological evaluations were conducted for the proband and his mother. We explored the pathogenesis of the variant by whole-cell patch clamp technique using HEK293T cells expressing the mutant Nav1.4 channel.Functional analysis of Nav1.4 with the V792G mutation revealed a hyperpolarized shift of voltage-dependent activation and fast inactivation. Moreover, steady-state slow inactivation in V792G was impaired with larger residual currents in comparison with wild-type Nav1.4.V792G in SCN4A is a pathogenic variant associated with the HyperPP phenotype and the inner pore lesion of Nav1.4 plays a crucial role in slow inactivation.
科研通智能强力驱动
Strongly Powered by AbleSci AI