A case of non-dystrophic myotonia with concomitant mutations in the SCN4A and CLCN1 genes

Kato, Hideki; Kokunai, Yosuke; Dalle, Carine; Kubota, Tomoya; Madokoro, Yuta; Yuasa, Hiroyuki; Uchida, Yuto; Ikeda, Tomomasa; Mochizuki, Hideki; Nicole, Sophie; Fontaine, Bertrand; Takahashi, Masanori; Mitake, Shigehisa

doi:10.1016/j.jns.2016.08.030

Cited by 20 publications

(14 citation statements)

References 23 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: Discussionsupporting

confidence: 67%

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: Discussionsupporting

confidence: 67%

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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“…Clinical, genetic and muscle excitability recordings suggest that the synonymous CLCN1 c.1650G>A variant is not functionally silent in our patient, and may act as a modifier to exacerbate the severity of myotonia. Other heterozygous CLCN1 mutations are known to modify the phenotype of sodium channel myotonia 18–20 . The CLCN1 c.1650G>A variant was previously reported in a pedigree with homozygous or compound heterozygous patients 13 .…”

Section: Discussionmentioning

confidence: 99%

Myotonia in a patient with a mutation in an S4 arginine residue associated with hypokalaemic periodic paralysis and a concomitant synonymous CLCN1 mutation

Thor

Vivekanandam

Sampedro‐Castañeda

et al. 2019

Sci Rep

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The sarcolemmal voltage gated sodium channel NaV1.4 conducts the key depolarizing current that drives the upstroke of the skeletal muscle action potential. It contains four voltage-sensing domains (VSDs) that regulate the opening of the pore domain and ensuing permeation of sodium ions. Mutations that lead to increased NaV1.4 currents are found in patients with myotonia or hyperkalaemic periodic paralysis (HyperPP). Myotonia is also caused by mutations in the CLCN1gene that result in loss-of-function of the skeletal muscle chloride channel ClC-1. Mutations affecting arginine residues in the fourth transmembrane helix (S4) of the NaV1.4 VSDs can result in a leak current through the VSD and hypokalemic periodic paralysis (HypoPP), but these have hitherto not been associated with myotonia. We report a patient with an Nav1.4 S4 arginine mutation, R222Q, presenting with severe myotonia without fulminant paralytic episodes. Other mutations affecting the same residue, R222W and R222G, have been found in patients with HypoPP. We show that R222Q channels have enhanced activation, consistent with myotonia, but also conduct a leak current. The patient carries a concomitant synonymous CLCN1 variant that likely worsens the myotonia and potentially contributes to the amelioration of muscle paralysis. Our data show phenotypic variability for different mutations affecting the same S4 arginine that have implications for clinical therapy.

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“…VI: 3 was affected with concomitant mutations in both the CLCN1 and SCN4A genes. Other researchers have also reported a few patients with the same genes mutated (Table 3) [15][16][17][18]. These patients showed an atypical phenotype, suggesting that concomitant mutations may act synergistically to influence the phenotype [19].…”

Section: Discussionmentioning

confidence: 88%

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

et al. 2020

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Myotonia congenita and hypokalemic periodic paralysis type 2 are both rare genetic channelopathies caused by mutations in the CLCN1 gene encoding voltage-gated chloride channel CLC-1 and the SCN4A gene encoding voltage-gated sodium channel Na v 1.4. The patients with concomitant mutations in both genes manifested different unique symptoms from mutations in these genes separately. Here, we describe a patient with myotonia and periodic paralysis in a consanguineous marriage pedigree. By using whole-exome sequencing, a novel F306S variant in the CLCN1 gene and a known R222W mutation in the SCN4A gene were identified in the pedigree. Patch clamp analysis revealed that the F306S mutant reduced the opening probability of CLC-1 and chloride conductance. Our study expanded the CLCN1 mutation database. We emphasized the value of whole-exome sequencing for differential diagnosis in atypical myotonic patients.

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A case of non-dystrophic myotonia with concomitant mutations in the SCN4A and CLCN1 genes

Cited by 20 publications

References 23 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

Myotonia in a patient with a mutation in an S4 arginine residue associated with hypokalaemic periodic paralysis and a concomitant synonymous CLCN1 mutation

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

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