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A novel loss-of-function mutation of the voltage-gated potassium channel Kv10.2 involved in epilepsy and autism

BACKGROUND: Novel developmental mutations associated with disease are a continuous challenge in medicine. Clinical consequences caused by these mutations include neuron and cognitive alterations that can lead to epilepsy or autism spectrum disorders. Often, it is difficult to identify the physiologi...

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Autores principales: Galán-Vidal, Jesús, Socuéllamos, Paula G., Baena-Nuevo, María, Contreras, Lizbeth, González, Teresa, Pérez-Poyato, María S., Valenzuela, Carmen, González-Lamuño, Domingo, Gandarillas, Alberto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9446776/
https://www.ncbi.nlm.nih.gov/pubmed/36068614
http://dx.doi.org/10.1186/s13023-022-02499-z
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author Galán-Vidal, Jesús
Socuéllamos, Paula G.
Baena-Nuevo, María
Contreras, Lizbeth
González, Teresa
Pérez-Poyato, María S.
Valenzuela, Carmen
González-Lamuño, Domingo
Gandarillas, Alberto
author_facet Galán-Vidal, Jesús
Socuéllamos, Paula G.
Baena-Nuevo, María
Contreras, Lizbeth
González, Teresa
Pérez-Poyato, María S.
Valenzuela, Carmen
González-Lamuño, Domingo
Gandarillas, Alberto
author_sort Galán-Vidal, Jesús
collection PubMed
description BACKGROUND: Novel developmental mutations associated with disease are a continuous challenge in medicine. Clinical consequences caused by these mutations include neuron and cognitive alterations that can lead to epilepsy or autism spectrum disorders. Often, it is difficult to identify the physiological defects and the appropriate treatments. RESULTS: We have isolated and cultured primary cells from the skin of a patient with combined epilepsy and autism syndrome. A mutation in the potassium channel protein Kv10.2 was identified. We have characterised the alteration of the mutant channel and found that it causes loss of function (LOF). Primary cells from the skin displayed a very striking growth defect and increased differentiation. In vitro treatment with various carbonic anhydrase inhibitors with various degrees of specificity for potassium channels, (Brinzolamide, Acetazolamide, Retigabine) restored the activation capacity of the mutated channel. Interestingly, the drugs also recovered in vitro the expansion capacity of the mutated skin cells. Furthermore, treatment with Acetazolamide clearly improved the patient regarding epilepsy and cognitive skills. When the treatment was temporarily halted the syndrome worsened again. CONCLUSIONS: By in vitro studying primary cells from the patient and the activation capacity of the mutated protein, we could first, find a readout for the cellular defects and second, test pharmaceutical treatments that proved to be beneficial. The results show the involvement of a novel LOF mutation of a Potassium channel in autism syndrome with epilepsy and the great potential of in vitro cultures of primary cells in personalised medicine of rare diseases.
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spelling pubmed-94467762022-09-07 A novel loss-of-function mutation of the voltage-gated potassium channel Kv10.2 involved in epilepsy and autism Galán-Vidal, Jesús Socuéllamos, Paula G. Baena-Nuevo, María Contreras, Lizbeth González, Teresa Pérez-Poyato, María S. Valenzuela, Carmen González-Lamuño, Domingo Gandarillas, Alberto Orphanet J Rare Dis Research BACKGROUND: Novel developmental mutations associated with disease are a continuous challenge in medicine. Clinical consequences caused by these mutations include neuron and cognitive alterations that can lead to epilepsy or autism spectrum disorders. Often, it is difficult to identify the physiological defects and the appropriate treatments. RESULTS: We have isolated and cultured primary cells from the skin of a patient with combined epilepsy and autism syndrome. A mutation in the potassium channel protein Kv10.2 was identified. We have characterised the alteration of the mutant channel and found that it causes loss of function (LOF). Primary cells from the skin displayed a very striking growth defect and increased differentiation. In vitro treatment with various carbonic anhydrase inhibitors with various degrees of specificity for potassium channels, (Brinzolamide, Acetazolamide, Retigabine) restored the activation capacity of the mutated channel. Interestingly, the drugs also recovered in vitro the expansion capacity of the mutated skin cells. Furthermore, treatment with Acetazolamide clearly improved the patient regarding epilepsy and cognitive skills. When the treatment was temporarily halted the syndrome worsened again. CONCLUSIONS: By in vitro studying primary cells from the patient and the activation capacity of the mutated protein, we could first, find a readout for the cellular defects and second, test pharmaceutical treatments that proved to be beneficial. The results show the involvement of a novel LOF mutation of a Potassium channel in autism syndrome with epilepsy and the great potential of in vitro cultures of primary cells in personalised medicine of rare diseases. BioMed Central 2022-09-06 /pmc/articles/PMC9446776/ /pubmed/36068614 http://dx.doi.org/10.1186/s13023-022-02499-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Galán-Vidal, Jesús
Socuéllamos, Paula G.
Baena-Nuevo, María
Contreras, Lizbeth
González, Teresa
Pérez-Poyato, María S.
Valenzuela, Carmen
González-Lamuño, Domingo
Gandarillas, Alberto
A novel loss-of-function mutation of the voltage-gated potassium channel Kv10.2 involved in epilepsy and autism
title A novel loss-of-function mutation of the voltage-gated potassium channel Kv10.2 involved in epilepsy and autism
title_full A novel loss-of-function mutation of the voltage-gated potassium channel Kv10.2 involved in epilepsy and autism
title_fullStr A novel loss-of-function mutation of the voltage-gated potassium channel Kv10.2 involved in epilepsy and autism
title_full_unstemmed A novel loss-of-function mutation of the voltage-gated potassium channel Kv10.2 involved in epilepsy and autism
title_short A novel loss-of-function mutation of the voltage-gated potassium channel Kv10.2 involved in epilepsy and autism
title_sort novel loss-of-function mutation of the voltage-gated potassium channel kv10.2 involved in epilepsy and autism
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9446776/
https://www.ncbi.nlm.nih.gov/pubmed/36068614
http://dx.doi.org/10.1186/s13023-022-02499-z
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