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Recurrent de novo mutations in CLDN5 induce an anion-selective blood–brain barrier and alternating hemiplegia

Claudin-5 is the most enriched tight junction protein at the blood–brain barrier. Perturbations in its levels of expression have been observed across numerous neurological and neuropsychiatric conditions; however, pathogenic variants in the coding sequence of the gene have never been reported previo...

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Autores principales: Hashimoto, Yosuke, Poirier, Karine, Boddaert, Nathalie, Hubert, Laurence, Aubart, Melodie, Kaminska, Anna, Alison, Marianne, Desguerre, Isabelle, Munnich, Arnold, Campbell, Matthew
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9586545/
https://www.ncbi.nlm.nih.gov/pubmed/35714222
http://dx.doi.org/10.1093/brain/awac215
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author Hashimoto, Yosuke
Poirier, Karine
Boddaert, Nathalie
Hubert, Laurence
Aubart, Melodie
Kaminska, Anna
Alison, Marianne
Desguerre, Isabelle
Munnich, Arnold
Campbell, Matthew
author_facet Hashimoto, Yosuke
Poirier, Karine
Boddaert, Nathalie
Hubert, Laurence
Aubart, Melodie
Kaminska, Anna
Alison, Marianne
Desguerre, Isabelle
Munnich, Arnold
Campbell, Matthew
author_sort Hashimoto, Yosuke
collection PubMed
description Claudin-5 is the most enriched tight junction protein at the blood–brain barrier. Perturbations in its levels of expression have been observed across numerous neurological and neuropsychiatric conditions; however, pathogenic variants in the coding sequence of the gene have never been reported previously. Here, we report the identification of a novel de novo mutation (c.178G>A) in the CLDN5 gene in two unrelated cases of alternating hemiplegia with microcephaly. This mutation (G60R) lies within the first extracellular loop of claudin-5 and based on protein modelling and sequence alignment, we predicted it would modify claudin-5 to become an anion-selective junctional component as opposed to a purely barrier-forming protein. Generation of stably transfected cell lines expressing wild-type or G60R claudin-5 showed that the tight junctions could still form in the presence of the G60R mutation but that the barrier against small molecules was clearly attenuated and displayed higher Cl(−) ion permeability and lower Na(+) permeability. While this study strongly suggests that CLDN5 associated alternating hemiplegia is a channelopathy, it is also the first study to identify the conversion of the blood–brain barrier to an anion-selective channel mediated by a dominant acting variant in CLDN5.
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spelling pubmed-95865452022-10-25 Recurrent de novo mutations in CLDN5 induce an anion-selective blood–brain barrier and alternating hemiplegia Hashimoto, Yosuke Poirier, Karine Boddaert, Nathalie Hubert, Laurence Aubart, Melodie Kaminska, Anna Alison, Marianne Desguerre, Isabelle Munnich, Arnold Campbell, Matthew Brain Report Claudin-5 is the most enriched tight junction protein at the blood–brain barrier. Perturbations in its levels of expression have been observed across numerous neurological and neuropsychiatric conditions; however, pathogenic variants in the coding sequence of the gene have never been reported previously. Here, we report the identification of a novel de novo mutation (c.178G>A) in the CLDN5 gene in two unrelated cases of alternating hemiplegia with microcephaly. This mutation (G60R) lies within the first extracellular loop of claudin-5 and based on protein modelling and sequence alignment, we predicted it would modify claudin-5 to become an anion-selective junctional component as opposed to a purely barrier-forming protein. Generation of stably transfected cell lines expressing wild-type or G60R claudin-5 showed that the tight junctions could still form in the presence of the G60R mutation but that the barrier against small molecules was clearly attenuated and displayed higher Cl(−) ion permeability and lower Na(+) permeability. While this study strongly suggests that CLDN5 associated alternating hemiplegia is a channelopathy, it is also the first study to identify the conversion of the blood–brain barrier to an anion-selective channel mediated by a dominant acting variant in CLDN5. Oxford University Press 2022-06-17 /pmc/articles/PMC9586545/ /pubmed/35714222 http://dx.doi.org/10.1093/brain/awac215 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Report
Hashimoto, Yosuke
Poirier, Karine
Boddaert, Nathalie
Hubert, Laurence
Aubart, Melodie
Kaminska, Anna
Alison, Marianne
Desguerre, Isabelle
Munnich, Arnold
Campbell, Matthew
Recurrent de novo mutations in CLDN5 induce an anion-selective blood–brain barrier and alternating hemiplegia
title Recurrent de novo mutations in CLDN5 induce an anion-selective blood–brain barrier and alternating hemiplegia
title_full Recurrent de novo mutations in CLDN5 induce an anion-selective blood–brain barrier and alternating hemiplegia
title_fullStr Recurrent de novo mutations in CLDN5 induce an anion-selective blood–brain barrier and alternating hemiplegia
title_full_unstemmed Recurrent de novo mutations in CLDN5 induce an anion-selective blood–brain barrier and alternating hemiplegia
title_short Recurrent de novo mutations in CLDN5 induce an anion-selective blood–brain barrier and alternating hemiplegia
title_sort recurrent de novo mutations in cldn5 induce an anion-selective blood–brain barrier and alternating hemiplegia
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9586545/
https://www.ncbi.nlm.nih.gov/pubmed/35714222
http://dx.doi.org/10.1093/brain/awac215
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