Myotonia congenita and periodic hypokalemia paralysis in a consanguineous marriage pedigree: Coexistence of a novel CLCN1 mutation and an SCN4A mutation

Zhao, Chenyu; Tang, Dongfang; Huang, Hui; Tang, Haiyan; Yang, Yuan; Yang, Min; Luo, Yingying; Tao, Huai; Tang, Jianguang; Zhou, Xi; Shi, Xiaoliu

doi:10.1371/journal.pone.0233017

Cited by 4 publications

(2 citation statements)

References 39 publications

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“…The coexistence of CLCN1 and SCN4A mutations has been described previously in atypical sodium channel diseases [ 51 , 52 , 53 ], or as recently reported, in a patient affected by MC and a sodium channelopathy [ 54 ]. In the former cases, the CLCN1 mutation might be acting as a disease modifier, and by triggering a synergic effect, could explain the atypical phenotype [ 3 , 51 , 52 , 53 ].…”

Section: Discussionmentioning

confidence: 71%

Functional and Structural Characterization of ClC-1 and Nav1.4 Channels Resulting from CLCN1 and SCN4A Mutations Identified Alone and Coexisting in Myotonic Patients

Brenes

Barbieri

Vásquez

et al. 2021

Cells

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Non-dystrophic myotonias have been linked to loss-of-function mutations in the ClC-1 chloride channel or gain-of-function mutations in the Nav1.4 sodium channel. Here, we describe a family with members diagnosed with Thomsen’s disease. One novel mutation (p.W322*) in CLCN1 and one undescribed mutation (p.R1463H) in SCN4A are segregating in this family. The CLCN1-p.W322* was also found in an unrelated family, in compound heterozygosity with the known CLCN1-p.G355R mutation. One reported mutation, SCN4A-p.T1313M, was found in a third family. Both CLCN1 mutations exhibited loss-of-function: CLCN1-p.W322* probably leads to a non-viable truncated protein; for CLCN1-p.G355R, we predict structural damage, triggering important steric clashes. The SCN4A-p.R1463H produced a positive shift in the steady-state inactivation increasing window currents and a faster recovery from inactivation. These gain-of-function effects are probably due to a disruption of interaction R1463-D1356, which destabilizes the voltage sensor domain (VSD) IV and increases the flexibility of the S4-S5 linker. Finally, modelling suggested that the p.T1313M induces a strong decrease in protein flexibility on the III-IV linker. This study demonstrates that CLCN1-p.W322* and SCN4A-p.R1463H mutations can act alone or in combination as inducers of myotonia. Their co-segregation highlights the necessity for carrying out deep genetic analysis to provide accurate genetic counseling and management of patients.

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Section: Discussionmentioning

confidence: 71%

Functional and Structural Characterization of ClC-1 and Nav1.4 Channels Resulting from CLCN1 and SCN4A Mutations Identified Alone and Coexisting in Myotonic Patients

Brenes

Barbieri

Vásquez

et al. 2021

Cells

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“…Also, mutations in helices C [64], G [65], and I and in the M-N loop [66,67] have been reported to alter ion selectivity (Supplementary Table S2). Nonetheless, more studies are necessary to clarify the role of helices C, G, and I and the M-N loop as part of the Cl − selectivity filter or if mutations indirectly alter its structure, for example, by analyzing mutations like G160H or C179W in helix C more deeply.…”

Section: Pore Propertiesmentioning

confidence: 99%

ClC-1 Chloride Channel: Inputs on the Structure–Function Relationship of Myotonia Congenita-Causing Mutations

Brenes,

Pusch,

Morales

2023

Biomedicines

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Myotonia congenita is a hereditary muscle disease mainly characterized by muscle hyperexcitability, which leads to a sustained burst of discharges that correlates with the magnitude and duration of involuntary aftercontractions, muscle stiffness, and hypertrophy. Mutations in the chloride voltage-gated channel 1 (CLCN1) gene that encodes the skeletal muscle chloride channel (ClC-1) are responsible for this disease, which is commonly known as myotonic chloride channelopathy. The biophysical properties of the mutated channel have been explored and analyzed through in vitro approaches, providing important clues to the general function/dysfunction of the wild-type and mutated channels. After an exhaustive search for CLCN1 mutations, we report in this review more than 350 different mutations identified in the literature. We start discussing the physiological role of the ClC-1 channel in skeletal muscle functioning. Then, using the reported functional effects of the naturally occurring mutations, we describe the biophysical and structural characteristics of the ClC-1 channel to update the knowledge of the function of each of the ClC-1 helices, and finally, we attempt to point out some patterns regarding the effects of mutations in the different helices and loops of the protein.

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Clinical and molecular characteristics of myotonia congenita in China: Case series and a literature review

Wang

et al. 2022

Channels

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Myotonia congenita and periodic hypokalemia paralysis in a consanguineous marriage pedigree: Coexistence of a novel CLCN1 mutation and an SCN4A mutation

Cited by 4 publications

References 39 publications

Functional and Structural Characterization of ClC-1 and Nav1.4 Channels Resulting from CLCN1 and SCN4A Mutations Identified Alone and Coexisting in Myotonic Patients

Functional and Structural Characterization of ClC-1 and Nav1.4 Channels Resulting from CLCN1 and SCN4A Mutations Identified Alone and Coexisting in Myotonic Patients

ClC-1 Chloride Channel: Inputs on the Structure–Function Relationship of Myotonia Congenita-Causing Mutations

Clinical and molecular characteristics of myotonia congenita in China: Case series and a literature review

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