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Article

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

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Departamento de Fisiología, Escuela de Medicina, Universidad de Costa Rica, 11501 San José, Costa Rica
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Centro de Investigación en Neurociencias (CIN), Universidad de Costa Rica, 11501 San José, Costa Rica
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Istituto di Biofisica, CNR, 16149 Genova, Italy
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Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, 11501 San José, Costa Rica
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Escuela de Biología, Universidad de Costa Rica, 11501 San José, Costa Rica
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Laboratorio de Neurofisiología (Neurolab), 11801 San José, Costa Rica
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Sección de Genética y Biotecnología, Escuela de Biología, Universidad de Costa Rica, 11501 San José, Costa Rica
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Scuola Internazionale Superiore di Studi Avanzati (SISSA), 34136 Trieste, Italy
*
Authors to whom correspondence should be addressed.
Cells 2021, 10(2), 374; https://doi.org/10.3390/cells10020374
Received: 16 December 2020 / Revised: 13 January 2021 / Accepted: 13 January 2021 / Published: 11 February 2021
(This article belongs to the Special Issue Skeletal Muscle Ion Channels in Health and Diseases)
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. View Full-Text
Keywords: myotonia; chloride channel; sodium channel; Xenopus oocytes; electrophysiology; structure analysis myotonia; chloride channel; sodium channel; Xenopus oocytes; electrophysiology; structure analysis
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MDPI and ACS Style

Brenes, O.; Barbieri, R.; Vásquez, M.; Vindas-Smith, R.; Roig, J.; Romero, A.; Valle, G.d.; Bermúdez-Guzmán, L.; Bertelli, S.; Pusch, M.; Morales, F. Functional and Structural Characterization of ClC-1 and Nav1.4 Channels Resulting from CLCN1 and SCN4A Mutations Identified Alone and Coexisting in Myotonic Patients. Cells 2021, 10, 374. https://doi.org/10.3390/cells10020374

AMA Style

Brenes O, Barbieri R, Vásquez M, Vindas-Smith R, Roig J, Romero A, Valle Gd, Bermúdez-Guzmán L, Bertelli S, Pusch M, Morales F. Functional and Structural Characterization of ClC-1 and Nav1.4 Channels Resulting from CLCN1 and SCN4A Mutations Identified Alone and Coexisting in Myotonic Patients. Cells. 2021; 10(2):374. https://doi.org/10.3390/cells10020374

Chicago/Turabian Style

Brenes, Oscar, Raffaella Barbieri, Melissa Vásquez, Rebeca Vindas-Smith, Jeffrey Roig, Adarli Romero, Gerardo d. Valle, Luis Bermúdez-Guzmán, Sara Bertelli, Michael Pusch, and Fernando Morales. 2021. "Functional and Structural Characterization of ClC-1 and Nav1.4 Channels Resulting from CLCN1 and SCN4A Mutations Identified Alone and Coexisting in Myotonic Patients" Cells 10, no. 2: 374. https://doi.org/10.3390/cells10020374

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