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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...

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Autores principales: Miceli, Francesco, Guerrini, Renzo, Nappi, Mario, Soldovieri, Maria Virginia, Cellini, Elena, Gurnett, Christina A., Parmeggiani, Lucio, Mei, Davide, Taglialatela, Maurizio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
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.
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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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