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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Veröffentlicht in:Brain (London, England : 1878) England : 1878), 2022-10, Vol.145 (10), p.3374-3382
Hauptverfasser: Hashimoto, Yosuke, Poirier, Karine, Boddaert, Nathalie, Hubert, Laurence, Aubart, Melodie, Kaminska, Anna, Alison, Marianne, Desguerre, Isabelle, Munnich, Arnold, Campbell, Matthew
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Sprache:eng
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Zusammenfassung: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.
ISSN:0006-8950
1460-2156
DOI:10.1093/brain/awac215