先天性肌强直的CLCN1突变具有可变的遗传模式，提示了一种新的显性肌强直机制。
CLCN1 Myotonia congenita mutation with a variable pattern of inheritance suggests a novel mechanism of dominant myotonia.
作者信息
Gaitán-Peñas Héctor, Armand-Ugón Mercedes, Macaya Alfons, Estévez Raúl
机构信息
Unitat de Fisiologia, Departament de Ciències Fisiològiques, IDIBELL-Universitat de Barcelona (Institut de Neurociències), L'Hospitalet de Llobregat, Spain.
U-750, CIBERER, ISCIII, Barcelona, Spain.
出版信息
Muscle Nerve. 2018 Feb 9. doi: 10.1002/mus.26098.
INTRODUCTION
Mutations in CLCN1 cause recessive or dominant forms of myotonia congenita (MC). Some mutations have been found to exhibit both patterns of inheritance but the mechanism explaining this behavior is unknown.
METHODS
A known recessive missense mutation, A493E, was identified in a family with dominant MC. The mutant p.A493E alone or in co-expression with wild-type (WT) ClC-1 was expressed in Xenopus oocytes. Currents were measured and biochemical assays were performed.
RESULTS
The mutant showed no significant activity and reduced total and plasma membrane (PM) protein levels. Co-expression with the mutant reduced the activity and PM levels of an engineered lower expression variant of ClC-1, whereas no effect was observed on a higher expression variant.
DISCUSSION
Our results suggest that the dominant effect of some CLCN1 mutations showing recessive or dominant inheritance patterns may be due to a dose-dependent defect in PM delivery of the WT channel. Muscle Nerve, 2018.
引言
CLCN1基因的突变会导致先天性肌强直（MC）的隐性或显性形式。已发现一些突变表现出两种遗传模式，但解释这种现象的机制尚不清楚。
方法
在一个显性MC家族中鉴定出一个已知的隐性错义突变A493E。将突变型p.A493E单独或与野生型（WT）ClC-1共表达于非洲爪蟾卵母细胞中。测量电流并进行生化分析。
结果
突变体显示无明显活性，且总蛋白水平和质膜（PM）蛋白水平降低。与突变体共表达会降低ClC-1工程化低表达变体的活性和PM水平，而对高表达变体未观察到影响。
讨论
我们的结果表明，一些表现出隐性或显性遗传模式的CLCN1突变的显性效应可能是由于野生型通道的质膜转运存在剂量依赖性缺陷。《肌肉与神经》，2018年。
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