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Substitutions of the S4DIV R2 residue (R1451) in Na(V)1.4 lead to complex forms of paramyotonia congenita and periodic paralyses
Mutations in Na(V)1.4, the skeletal muscle voltage-gated Na(+) channel, underlie several skeletal muscle channelopathies. We report here the functional characterization of two substitutions targeting the R1451 residue and resulting in 3 distinct clinical phenotypes. The R1451L is a novel pathogenic...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794747/ https://www.ncbi.nlm.nih.gov/pubmed/29391559 http://dx.doi.org/10.1038/s41598-018-20468-0 |
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author | Poulin, Hugo Gosselin-Badaroudine, Pascal Vicart, Savine Habbout, Karima Sternberg, Damien Giuliano, Serena Fontaine, Bertrand Bendahhou, Saïd Nicole, Sophie Chahine, Mohamed |
author_facet | Poulin, Hugo Gosselin-Badaroudine, Pascal Vicart, Savine Habbout, Karima Sternberg, Damien Giuliano, Serena Fontaine, Bertrand Bendahhou, Saïd Nicole, Sophie Chahine, Mohamed |
author_sort | Poulin, Hugo |
collection | PubMed |
description | Mutations in Na(V)1.4, the skeletal muscle voltage-gated Na(+) channel, underlie several skeletal muscle channelopathies. We report here the functional characterization of two substitutions targeting the R1451 residue and resulting in 3 distinct clinical phenotypes. The R1451L is a novel pathogenic substitution found in two unrelated individuals. The first individual was diagnosed with non-dystrophic myotonia, whereas the second suffered from an unusual phenotype combining hyperkalemic and hypokalemic episodes of periodic paralysis (PP). The R1451C substitution was found in one individual with a single attack of hypoPP induced by glucocorticoids. To elucidate the biophysical mechanism underlying the phenotypes, we used the patch-clamp technique to study tsA201 cells expressing WT or R1451C/L channels. Our results showed that both substitutions shifted the inactivation to hyperpolarized potentials, slowed the kinetics of inactivation, slowed the recovery from slow inactivation and reduced the current density. Cooling further enhanced these abnormalities. Homology modeling revealed a disruption of hydrogen bonds in the voltage sensor domain caused by R1451C/L. We concluded that the altered biophysical properties of R1451C/L well account for the PMC-hyperPP cluster and that additional factors likely play a critical role in the inter-individual differences of clinical expression resulting from R1451C/L. |
format | Online Article Text |
id | pubmed-5794747 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-57947472018-02-12 Substitutions of the S4DIV R2 residue (R1451) in Na(V)1.4 lead to complex forms of paramyotonia congenita and periodic paralyses Poulin, Hugo Gosselin-Badaroudine, Pascal Vicart, Savine Habbout, Karima Sternberg, Damien Giuliano, Serena Fontaine, Bertrand Bendahhou, Saïd Nicole, Sophie Chahine, Mohamed Sci Rep Article Mutations in Na(V)1.4, the skeletal muscle voltage-gated Na(+) channel, underlie several skeletal muscle channelopathies. We report here the functional characterization of two substitutions targeting the R1451 residue and resulting in 3 distinct clinical phenotypes. The R1451L is a novel pathogenic substitution found in two unrelated individuals. The first individual was diagnosed with non-dystrophic myotonia, whereas the second suffered from an unusual phenotype combining hyperkalemic and hypokalemic episodes of periodic paralysis (PP). The R1451C substitution was found in one individual with a single attack of hypoPP induced by glucocorticoids. To elucidate the biophysical mechanism underlying the phenotypes, we used the patch-clamp technique to study tsA201 cells expressing WT or R1451C/L channels. Our results showed that both substitutions shifted the inactivation to hyperpolarized potentials, slowed the kinetics of inactivation, slowed the recovery from slow inactivation and reduced the current density. Cooling further enhanced these abnormalities. Homology modeling revealed a disruption of hydrogen bonds in the voltage sensor domain caused by R1451C/L. We concluded that the altered biophysical properties of R1451C/L well account for the PMC-hyperPP cluster and that additional factors likely play a critical role in the inter-individual differences of clinical expression resulting from R1451C/L. Nature Publishing Group UK 2018-02-01 /pmc/articles/PMC5794747/ /pubmed/29391559 http://dx.doi.org/10.1038/s41598-018-20468-0 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Poulin, Hugo Gosselin-Badaroudine, Pascal Vicart, Savine Habbout, Karima Sternberg, Damien Giuliano, Serena Fontaine, Bertrand Bendahhou, Saïd Nicole, Sophie Chahine, Mohamed Substitutions of the S4DIV R2 residue (R1451) in Na(V)1.4 lead to complex forms of paramyotonia congenita and periodic paralyses |
title | Substitutions of the S4DIV R2 residue (R1451) in Na(V)1.4 lead to complex forms of paramyotonia congenita and periodic paralyses |
title_full | Substitutions of the S4DIV R2 residue (R1451) in Na(V)1.4 lead to complex forms of paramyotonia congenita and periodic paralyses |
title_fullStr | Substitutions of the S4DIV R2 residue (R1451) in Na(V)1.4 lead to complex forms of paramyotonia congenita and periodic paralyses |
title_full_unstemmed | Substitutions of the S4DIV R2 residue (R1451) in Na(V)1.4 lead to complex forms of paramyotonia congenita and periodic paralyses |
title_short | Substitutions of the S4DIV R2 residue (R1451) in Na(V)1.4 lead to complex forms of paramyotonia congenita and periodic paralyses |
title_sort | substitutions of the s4div r2 residue (r1451) in na(v)1.4 lead to complex forms of paramyotonia congenita and periodic paralyses |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794747/ https://www.ncbi.nlm.nih.gov/pubmed/29391559 http://dx.doi.org/10.1038/s41598-018-20468-0 |
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