Phenotypic and functional assessment of two novel KCNQ2 gain-of-function variants Y141N and G239S and effects of amitriptyline treatment
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Le résumé fourni par la source
While loss-of-function (LoF) variants in KCNQ2 are associated with a spectrum of neonatal-onset epilepsies, gain-of-function (GoF) variants cause a more complex phenotype that precludes neonatal-onset epilepsy. In the present work, the clinical features of three patients carrying a de novo KCNQ2 Y141N (n = 1) or G239S variant (n = 2) respectively, are described. All three patients had a mild global developmental delay, with prominent language deficits, and strong activation of interictal epileptic activity during sleep. Epileptic seizures were not reported. The absence of neonatal seizures suggested a GoF effect and prompted functional testing of the variants. In vitro whole-cell patch-clamp electrophysiological experiments in Chinese Hamster Ovary cells transiently-transfected with the cDNAs encoding Kv7.2 subunits carrying the Y141N or G239S variants in homomeric or heteromeric configurations with Kv7.2 subunits, revealed that currents from channels incorporating mutant subunits displayed increased current densities and hyperpolarizing shifts of about 10 mV in activation gating; both these functional features are consistent with an in vitro GoF phenotype. The antidepressant drug amitriptyline induced a reversible and concentration-dependent inhibition of current carried by Kv7.2 Y141N and G239S mutant channels. Based on in vitro results, amitriptyline was prescribed in one patient (G239S), prompting a significant improvement in motor, verbal, social, sensory and adaptive behavior skillsduring the two-year-treatment period. Thus, our results suggest that KCNQ2 GoF variants Y141N and G239S cause a mild DD with prominent language deficits in the absence of neonatal seizures and that treatment with the Kv7 channel blocker amitriptyline might represent a potential targeted treatment for patients with KCNQ2 GoF variants.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Phenotypic and functional assessment of two novel KCNQ2 gain-of-function variants Y141N and G239S and effects of amitriptyline treatment
- Date Crossref
- 01/01/2024
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Copenhagen Department of Drug Design and Pharmacology pays non établi dans la noticeUniversité ou école supérieure
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University of Southern Denmark Department of Epilepsy Genetics and Personalized Medicine pays non établi dans la noticeUniversité ou école supérieure
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Filadelfia pays non établi dans la noticeOrganisation à but non lucratif
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University of Naples Federico II pays non établi dans la noticeUniversité ou école supérieure
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Rigshospitalet pays non établi dans la noticeÉtablissement de santé
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Medical University of Warsaw Department of Medical Genetics pays non établi dans la noticeUniversité ou école supérieure
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Baylor College of Medicine Departments of Neurology pays non établi dans la noticeUniversité ou école supérieure
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University of Antwerp VIB pays non établi dans la noticeUniversité ou école supérieure
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Antwerp University Hospital pays non établi dans la noticeOrganisme public
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VIB-UAntwerp Center for Molecular Neurology pays non établi dans la noticeStructure de recherche
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Department of Epilepsy Genetics and Personalized Medicine pays non établi dans la noticeInstitution
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University of Naples "Federico II" Department of Neuroscience pays non établi dans la noticeUniversité ou école supérieure
Department of Drug Design and Pharmacology — University of Copenhagen, Department of Epilepsy Genetics and Personalized Medicine — University of Southern Denmark et Filadelfia, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.