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Distinct epilepsy phenotypes and response to drugs in KCNA1 gain‐ and loss‐of function variants
A wide phenotypic spectrum of neurological diseases is associated with KCNA1 (Kv1.1) variants. To investigate the molecular basis of such a heterogeneous clinical presentation and identify the possible correlation with in vitro phenotypes, we compared the functional consequences of three heterozygou...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299230/ https://www.ncbi.nlm.nih.gov/pubmed/34778950 http://dx.doi.org/10.1111/epi.17118 |
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author | Miceli, Francesco Guerrini, Renzo Nappi, Mario Soldovieri, Maria Virginia Cellini, Elena Gurnett, Christina A. Parmeggiani, Lucio Mei, Davide Taglialatela, Maurizio |
author_facet | Miceli, Francesco Guerrini, Renzo Nappi, Mario Soldovieri, Maria Virginia Cellini, Elena Gurnett, Christina A. Parmeggiani, Lucio Mei, Davide Taglialatela, Maurizio |
author_sort | Miceli, Francesco |
collection | PubMed |
description | A wide phenotypic spectrum of neurological diseases is associated with KCNA1 (Kv1.1) variants. To investigate the molecular basis of such a heterogeneous clinical presentation and identify the possible correlation with in vitro phenotypes, we compared the functional consequences of three heterozygous de novo variants (p.P403S, p.P405L, and p.P405S) in Kv1.1 pore region found in four patients with severe developmental and epileptic encephalopathy (DEE), with those of a de novo variant in the voltage sensor (p.A261T) identified in two patients with mild, carbamazepine‐responsive, focal epilepsy. Patch‐clamp electrophysiology was used to investigate the functional properties of mutant Kv1.1 subunits, both expressed as homomers and heteromers with wild‐type Kv1.1 subunits. KCNA1 pore mutations markedly decreased (p. P405S) or fully suppressed (p. P403S, p. P405L) Kv1.1‐mediated currents, exerting loss‐of‐function (LoF) effects. By contrast, channels carrying the p.A261T variant exhibited a hyperpolarizing shift of the activation process, consistent with a gain‐of‐function (GoF) effect. The present results unveil a novel correlation between in vitro phenotype (GoF vs LoF) and clinical course (mild vs severe) in KCNA1‐related phenotypes. The excellent clinical response to carbamazepine observed in the patients carrying the A261T variant suggests an exquisite sensitivity of KCNA1 GoF to sodium channel inhibition that should be further explored. |
format | Online Article Text |
id | pubmed-9299230 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92992302022-07-21 Distinct epilepsy phenotypes and response to drugs in KCNA1 gain‐ and loss‐of function variants Miceli, Francesco Guerrini, Renzo Nappi, Mario Soldovieri, Maria Virginia Cellini, Elena Gurnett, Christina A. Parmeggiani, Lucio Mei, Davide Taglialatela, Maurizio Epilepsia Brief Communication A wide phenotypic spectrum of neurological diseases is associated with KCNA1 (Kv1.1) variants. To investigate the molecular basis of such a heterogeneous clinical presentation and identify the possible correlation with in vitro phenotypes, we compared the functional consequences of three heterozygous de novo variants (p.P403S, p.P405L, and p.P405S) in Kv1.1 pore region found in four patients with severe developmental and epileptic encephalopathy (DEE), with those of a de novo variant in the voltage sensor (p.A261T) identified in two patients with mild, carbamazepine‐responsive, focal epilepsy. Patch‐clamp electrophysiology was used to investigate the functional properties of mutant Kv1.1 subunits, both expressed as homomers and heteromers with wild‐type Kv1.1 subunits. KCNA1 pore mutations markedly decreased (p. P405S) or fully suppressed (p. P403S, p. P405L) Kv1.1‐mediated currents, exerting loss‐of‐function (LoF) effects. By contrast, channels carrying the p.A261T variant exhibited a hyperpolarizing shift of the activation process, consistent with a gain‐of‐function (GoF) effect. The present results unveil a novel correlation between in vitro phenotype (GoF vs LoF) and clinical course (mild vs severe) in KCNA1‐related phenotypes. The excellent clinical response to carbamazepine observed in the patients carrying the A261T variant suggests an exquisite sensitivity of KCNA1 GoF to sodium channel inhibition that should be further explored. John Wiley and Sons Inc. 2021-11-14 2022-01 /pmc/articles/PMC9299230/ /pubmed/34778950 http://dx.doi.org/10.1111/epi.17118 Text en © 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Brief Communication Miceli, Francesco Guerrini, Renzo Nappi, Mario Soldovieri, Maria Virginia Cellini, Elena Gurnett, Christina A. Parmeggiani, Lucio Mei, Davide Taglialatela, Maurizio Distinct epilepsy phenotypes and response to drugs in KCNA1 gain‐ and loss‐of function variants |
title | Distinct epilepsy phenotypes and response to drugs in KCNA1 gain‐ and loss‐of function variants |
title_full | Distinct epilepsy phenotypes and response to drugs in KCNA1 gain‐ and loss‐of function variants |
title_fullStr | Distinct epilepsy phenotypes and response to drugs in KCNA1 gain‐ and loss‐of function variants |
title_full_unstemmed | Distinct epilepsy phenotypes and response to drugs in KCNA1 gain‐ and loss‐of function variants |
title_short | Distinct epilepsy phenotypes and response to drugs in KCNA1 gain‐ and loss‐of function variants |
title_sort | distinct epilepsy phenotypes and response to drugs in kcna1 gain‐ and loss‐of function variants |
topic | Brief Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299230/ https://www.ncbi.nlm.nih.gov/pubmed/34778950 http://dx.doi.org/10.1111/epi.17118 |
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