Dataset Information

Electrophysiological characteristics of R47W and A298T mutations in CLC-1 of myotonia congenita patients and evaluation of clinical features.

ABSTRACT: Myotonia congenita (MC) is a genetic disease that displays impaired relaxation of skeletal muscle and muscle hypertrophy. This disease is mainly caused by mutations of CLCN1 that encodes human skeletal muscle chloride channel (CLC-1). CLC-1 is a voltage gated chloride channel that activates upon depolarizing potentials and play a major role in stabilization of resting membrane potentials in skeletal muscle. In this study, we report 4 unrelated Korean patients diagnosed with myotonia congenita and their clinical features. Sequence analysis of all coding regions of the patients was performed and mutation, R47W and A298T, was commonly identified. The patients commonly displayed transient muscle weakness and only one patient was diagnosed with autosomal dominant type of myotonia congenita. To investigate the pathological role of the mutation, electrophysiological analysis was also performed in HEK 293 cells transiently expressing homo- or heterodimeric mutant channels. The mutant channels displayed reduced chloride current density and altered channel gating. However, the effect of A298T on channel gating was reduced with the presence of R47W in the same allele. This analysis suggests that impaired CLC-1 channel function can cause myotonia congenita and that R47W has a protective effect on A298T in relation to channel gating. Our results provide clinical features of Korean myotonia congenita patients who have the heterozygous mutation and reveal underlying pathophyological consequences of the mutants by taking electrophysiological approach.

SUBMITTER: Chin HJ

PROVIDER: S-EPMC5507783 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Electrophysiological characteristics of R47W and A298T mutations in CLC-1 of myotonia congenita patients and evaluation of clinical features.

Chin Hyung Jin HJ Kim Chan Hyeong CH Ha Kotdaji K Shin Jin Hong JH Kim Dae-Seong DS So Insuk I

The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 20170626 4

Myotonia congenita (MC) is a genetic disease that displays impaired relaxation of skeletal muscle and muscle hypertrophy. This disease is mainly caused by mutations of <i>CLCN1</i> that encodes human skeletal muscle chloride channel (CLC-1). CLC-1 is a voltage gated chloride channel that activates upon depolarizing potentials and play a major role in stabilization of resting membrane potentials in skeletal muscle. In this study, we report 4 unrelated Korean patients diagnosed with myotonia conge ...[more]

PMID: 28706458

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Project description:The voltage-dependent ClC-1 chloride channel, whose open probability increases with membrane potential depolarization, belongs to the superfamily of CLC channels/transporters. ClC-1 is almost exclusively expressed in skeletal muscles and is essential for stabilizing the excitability of muscle membranes. Elucidation of the molecular structures of human ClC-1 and several CLC homologs provides important insight to the gating and ion permeation mechanisms of this chloride channel. Mutations in the human CLCN1 gene, which encodes the ClC-1 channel, are associated with a hereditary skeletal muscle disease, myotonia congenita. Most disease-causing CLCN1 mutations lead to loss-of-function phenotypes in the ClC-1 channel and thus increase membrane excitability in skeletal muscles, consequently manifesting as delayed relaxations following voluntary muscle contractions in myotonic subjects. The inheritance pattern of myotonia congenita can be autosomal dominant (Thomsen type) or recessive (Becker type). To date over 200 myotonia-associated ClC-1 mutations have been identified, which are scattered throughout the entire protein sequence. The dominant inheritance pattern of some myotonia mutations may be explained by a dominant-negative effect on ClC-1 channel gating. For many other myotonia mutations, however, no clear relationship can be established between the inheritance pattern and the location of the mutation in the ClC-1 protein. Emerging evidence indicates that the effects of some mutations may entail impaired ClC-1 protein homeostasis (proteostasis). Proteostasis of membrane proteins comprises of biogenesis at the endoplasmic reticulum (ER), trafficking to the surface membrane, and protein turn-over at the plasma membrane. Maintenance of proteostasis requires the coordination of a wide variety of different molecular chaperones and protein quality control factors. A number of regulatory molecules have recently been shown to contribute to post-translational modifications of ClC-1 and play critical roles in the ER quality control, membrane trafficking, and peripheral quality control of this chloride channel. Further illumination of the mechanisms of ClC-1 proteostasis network will enhance our understanding of the molecular pathophysiology of myotonia congenita, and may also bring to light novel therapeutic targets for skeletal muscle dysfunction caused by myotonia and other pathological conditions.

Project description:Background: CLCN1-related myotonia congenita (MC) is one of the most common forms of non-dystrophic myotonia, in which muscle relaxation is delayed after voluntary or evoked contraction. However, there is limited data of clinical and molecular spectrum of MC patients in China. Patients and Methods: Five patients with myotonia congenita due to mutations in CLCN1 gene were enrolled, which were identified through trio-whole-exome sequencing or panel-based next-generation sequencing test. The clinical presentation, laboratory data, electrophysiological tests, muscular pathology feature, and genetic results were collected and reviewed. We also searched all previously reported cases of MC patients with genetic diagnosis in Chinese populations, and their data were reviewed. Results: The median onset age of five patients was 3.0 years old, ranging from 1.0 to 5.0 years old, while the median age of admit was 5.0 years old, ranging from 3.5 to 8.8 years old. Five patients complained of muscle stiffness when rising from chairs or starting to climb stairs (5/5, 100.0%), four patients complained of delayed relaxation of their hands after forceful grip (4/5, 80.0%), all of which improved with exercise (warm-up phenomenon) (5/5, 100%). Electromyogram was conducted in five patients, which all revealed myotonic change (100%). Genetic tests revealed nine potential disease-causing variants in CLCN1 gene, including two novel variants: c.962T>A (p.V321E) and c.1250A>T (p.E417V). Literature review showed that 43 MC Chinese patients with genetic diagnosis have been reported till now (including our five patients). Forty-seven variants in CLCN1 gene were found, which consisted of 33 missense variants, 6 nonsense variants, 5 frame-shift variants, and 3 splicing variants. Variants in exon 8, 15, 12, and 16 were most prevalent, while the most common variants were c.892G>A (p.A298T) (n = 9), c.139C>T (p.R47W) (n = 3), c.1205C>T(p.A402V) (n = 3), c.1657A>T (p.I553F) (n = 3), c.1679T>C (p.M560T) (n = 3), c.350A>G (p.D117G) (n = 2), c.762C>G (p.C254W) (n = 2), c.782A>G (P.Y261C) (n = 2), and c.1277C>A (p.T426N) (n = 2). Conclusion: Our results reported five CLCN1-related MC patients, which expanded the clinical and genetic spectrum of MC patients in China. Based on literature review, 43MC Chinese patients with genetic diagnosis have been reported till now, and variants in exon eight were most prevalent in Chinese MC patients while c.892G>A (p.A298T) was probably a founder mutation.

Dataset Information

Electrophysiological characteristics of R47W and A298T mutations in CLC-1 of myotonia congenita patients and evaluation of clinical features.

Publications

Electrophysiological characteristics of R47W and A298T mutations in CLC-1 of myotonia congenita patients and evaluation of clinical features.

Similar Datasets

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