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Early-onset epileptic encephalopathy caused by a reduced sensitivity of Kv7.2 potassium channels to phosphatidylinositol 4,5-bisphosphate
Kv7.2 and Kv7.3 subunits underlie the M-current, a neuronal K(+) current characterized by an absolute functional requirement for phosphatidylinositol 4,5-bisphosphate (PIP(2)). Kv7.2 gene mutations cause early-onset neonatal seizures with heterogeneous clinical outcomes, ranging from self-limiting b...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131271/ https://www.ncbi.nlm.nih.gov/pubmed/27905566 http://dx.doi.org/10.1038/srep38167 |
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author | Soldovieri, Maria Virginia Ambrosino, Paolo Mosca, Ilaria De Maria, Michela Moretto, Edoardo Miceli, Francesco Alaimo, Alessandro Iraci, Nunzio Manocchio, Laura Medoro, Alessandro Passafaro, Maria Taglialatela, Maurizio |
author_facet | Soldovieri, Maria Virginia Ambrosino, Paolo Mosca, Ilaria De Maria, Michela Moretto, Edoardo Miceli, Francesco Alaimo, Alessandro Iraci, Nunzio Manocchio, Laura Medoro, Alessandro Passafaro, Maria Taglialatela, Maurizio |
author_sort | Soldovieri, Maria Virginia |
collection | PubMed |
description | Kv7.2 and Kv7.3 subunits underlie the M-current, a neuronal K(+) current characterized by an absolute functional requirement for phosphatidylinositol 4,5-bisphosphate (PIP(2)). Kv7.2 gene mutations cause early-onset neonatal seizures with heterogeneous clinical outcomes, ranging from self-limiting benign familial neonatal seizures to severe early-onset epileptic encephalopathy (Kv7.2-EE). In this study, the biochemical and functional consequences prompted by a recurrent variant (R325G) found independently in four individuals with severe forms of neonatal-onset EE have been investigated. Upon heterologous expression, homomeric Kv7.2 R325G channels were non-functional, despite biotin-capture in Western blots revealed normal plasma membrane subunit expression. Mutant subunits exerted dominant-negative effects when incorporated into heteromeric channels with Kv7.2 and/or Kv7.3 subunits. Increasing cellular PIP(2) levels by co-expression of type 1γ PI(4)P5-kinase (PIP5K) partially recovered homomeric Kv7.2 R325G channel function. Currents carried by heteromeric channels incorporating Kv7.2 R325G subunits were more readily inhibited than wild-type channels upon activation of a voltage-sensitive phosphatase (VSP), and recovered more slowly upon VSP switch-off. These results reveal for the first time that a mutation-induced decrease in current sensitivity to PIP(2) is the primary molecular defect responsible for Kv7.2-EE in individuals carrying the R325G variant, further expanding the range of pathogenetic mechanisms exploitable for personalized treatment of Kv7.2-related epilepsies. |
format | Online Article Text |
id | pubmed-5131271 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-51312712016-12-15 Early-onset epileptic encephalopathy caused by a reduced sensitivity of Kv7.2 potassium channels to phosphatidylinositol 4,5-bisphosphate Soldovieri, Maria Virginia Ambrosino, Paolo Mosca, Ilaria De Maria, Michela Moretto, Edoardo Miceli, Francesco Alaimo, Alessandro Iraci, Nunzio Manocchio, Laura Medoro, Alessandro Passafaro, Maria Taglialatela, Maurizio Sci Rep Article Kv7.2 and Kv7.3 subunits underlie the M-current, a neuronal K(+) current characterized by an absolute functional requirement for phosphatidylinositol 4,5-bisphosphate (PIP(2)). Kv7.2 gene mutations cause early-onset neonatal seizures with heterogeneous clinical outcomes, ranging from self-limiting benign familial neonatal seizures to severe early-onset epileptic encephalopathy (Kv7.2-EE). In this study, the biochemical and functional consequences prompted by a recurrent variant (R325G) found independently in four individuals with severe forms of neonatal-onset EE have been investigated. Upon heterologous expression, homomeric Kv7.2 R325G channels were non-functional, despite biotin-capture in Western blots revealed normal plasma membrane subunit expression. Mutant subunits exerted dominant-negative effects when incorporated into heteromeric channels with Kv7.2 and/or Kv7.3 subunits. Increasing cellular PIP(2) levels by co-expression of type 1γ PI(4)P5-kinase (PIP5K) partially recovered homomeric Kv7.2 R325G channel function. Currents carried by heteromeric channels incorporating Kv7.2 R325G subunits were more readily inhibited than wild-type channels upon activation of a voltage-sensitive phosphatase (VSP), and recovered more slowly upon VSP switch-off. These results reveal for the first time that a mutation-induced decrease in current sensitivity to PIP(2) is the primary molecular defect responsible for Kv7.2-EE in individuals carrying the R325G variant, further expanding the range of pathogenetic mechanisms exploitable for personalized treatment of Kv7.2-related epilepsies. Nature Publishing Group 2016-12-01 /pmc/articles/PMC5131271/ /pubmed/27905566 http://dx.doi.org/10.1038/srep38167 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Soldovieri, Maria Virginia Ambrosino, Paolo Mosca, Ilaria De Maria, Michela Moretto, Edoardo Miceli, Francesco Alaimo, Alessandro Iraci, Nunzio Manocchio, Laura Medoro, Alessandro Passafaro, Maria Taglialatela, Maurizio Early-onset epileptic encephalopathy caused by a reduced sensitivity of Kv7.2 potassium channels to phosphatidylinositol 4,5-bisphosphate |
title | Early-onset epileptic encephalopathy caused by a reduced sensitivity of Kv7.2 potassium channels to phosphatidylinositol 4,5-bisphosphate |
title_full | Early-onset epileptic encephalopathy caused by a reduced sensitivity of Kv7.2 potassium channels to phosphatidylinositol 4,5-bisphosphate |
title_fullStr | Early-onset epileptic encephalopathy caused by a reduced sensitivity of Kv7.2 potassium channels to phosphatidylinositol 4,5-bisphosphate |
title_full_unstemmed | Early-onset epileptic encephalopathy caused by a reduced sensitivity of Kv7.2 potassium channels to phosphatidylinositol 4,5-bisphosphate |
title_short | Early-onset epileptic encephalopathy caused by a reduced sensitivity of Kv7.2 potassium channels to phosphatidylinositol 4,5-bisphosphate |
title_sort | early-onset epileptic encephalopathy caused by a reduced sensitivity of kv7.2 potassium channels to phosphatidylinositol 4,5-bisphosphate |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131271/ https://www.ncbi.nlm.nih.gov/pubmed/27905566 http://dx.doi.org/10.1038/srep38167 |
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