Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease

Numerous SCN8A mutations have been identified, of which, the majority are de novo missense variants. Most mutations result in epileptic encephalopathy; however, some are associated with less severe phenotypes. Mouse models generated by knock-in of human missense SCN8A mutations exhibit seizures and...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Jennifer C. Wong, Kameryn M. Butler, Lindsey Shapiro, Jacquelyn T. Thelin, Kari A. Mattison, Kathryn B. Garber, Paula C. Goldenberg, Shobana Kubendran, G. Bradley Schaefer, Andrew Escayg
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	SCN8A sodium channel epilepsy seizure mouse mutation Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/f765ae8f391a48a3a868a1a5685cd432
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:f765ae8f391a48a3a868a1a5685cd432
record_format	dspace
spelling	oai:doaj.org-article:f765ae8f391a48a3a868a1a5685cd4322021-11-17T06:22:28ZPathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease1663-981210.3389/fphar.2021.748415https://doaj.org/article/f765ae8f391a48a3a868a1a5685cd4322021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.748415/fullhttps://doaj.org/toc/1663-9812Numerous SCN8A mutations have been identified, of which, the majority are de novo missense variants. Most mutations result in epileptic encephalopathy; however, some are associated with less severe phenotypes. Mouse models generated by knock-in of human missense SCN8A mutations exhibit seizures and a range of behavioral abnormalities. To date, there are only a few Scn8a mouse models with in-frame deletions or insertions, and notably, none of these mouse lines exhibit increased seizure susceptibility. In the current study, we report the generation and characterization of two Scn8a mouse models (ΔIRL/+ and ΔVIR/+) carrying overlapping in-frame deletions within the voltage sensor of domain 4 (DIVS4). Both mouse lines show increased seizure susceptibility and infrequent spontaneous seizures. We also describe two unrelated patients with the same in-frame SCN8A deletion in the DIV S5-S6 pore region, highlighting the clinical relevance of this class of mutations.Jennifer C. WongKameryn M. ButlerKameryn M. ButlerLindsey ShapiroJacquelyn T. ThelinKari A. MattisonKathryn B. GarberPaula C. GoldenbergShobana KubendranG. Bradley SchaeferAndrew EscaygFrontiers Media S.A.articleSCN8Asodium channelepilepsyseizuremousemutationTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	SCN8A sodium channel epilepsy seizure mouse mutation Therapeutics. Pharmacology RM1-950
spellingShingle	SCN8A sodium channel epilepsy seizure mouse mutation Therapeutics. Pharmacology RM1-950 Jennifer C. Wong Kameryn M. Butler Kameryn M. Butler Lindsey Shapiro Jacquelyn T. Thelin Kari A. Mattison Kathryn B. Garber Paula C. Goldenberg Shobana Kubendran G. Bradley Schaefer Andrew Escayg Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease
description	Numerous SCN8A mutations have been identified, of which, the majority are de novo missense variants. Most mutations result in epileptic encephalopathy; however, some are associated with less severe phenotypes. Mouse models generated by knock-in of human missense SCN8A mutations exhibit seizures and a range of behavioral abnormalities. To date, there are only a few Scn8a mouse models with in-frame deletions or insertions, and notably, none of these mouse lines exhibit increased seizure susceptibility. In the current study, we report the generation and characterization of two Scn8a mouse models (ΔIRL/+ and ΔVIR/+) carrying overlapping in-frame deletions within the voltage sensor of domain 4 (DIVS4). Both mouse lines show increased seizure susceptibility and infrequent spontaneous seizures. We also describe two unrelated patients with the same in-frame SCN8A deletion in the DIV S5-S6 pore region, highlighting the clinical relevance of this class of mutations.
format	article
author	Jennifer C. Wong Kameryn M. Butler Kameryn M. Butler Lindsey Shapiro Jacquelyn T. Thelin Kari A. Mattison Kathryn B. Garber Paula C. Goldenberg Shobana Kubendran G. Bradley Schaefer Andrew Escayg
author_facet	Jennifer C. Wong Kameryn M. Butler Kameryn M. Butler Lindsey Shapiro Jacquelyn T. Thelin Kari A. Mattison Kathryn B. Garber Paula C. Goldenberg Shobana Kubendran G. Bradley Schaefer Andrew Escayg
author_sort	Jennifer C. Wong
title	Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease
title_short	Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease
title_full	Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease
title_fullStr	Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease
title_full_unstemmed	Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease
title_sort	pathogenic in-frame variants in scn8a: expanding the genetic landscape of scn8a-associated disease
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/f765ae8f391a48a3a868a1a5685cd432
work_keys_str_mv	AT jennifercwong pathogenicinframevariantsinscn8aexpandingthegeneticlandscapeofscn8aassociateddisease AT kamerynmbutler pathogenicinframevariantsinscn8aexpandingthegeneticlandscapeofscn8aassociateddisease AT kamerynmbutler pathogenicinframevariantsinscn8aexpandingthegeneticlandscapeofscn8aassociateddisease AT lindseyshapiro pathogenicinframevariantsinscn8aexpandingthegeneticlandscapeofscn8aassociateddisease AT jacquelyntthelin pathogenicinframevariantsinscn8aexpandingthegeneticlandscapeofscn8aassociateddisease AT kariamattison pathogenicinframevariantsinscn8aexpandingthegeneticlandscapeofscn8aassociateddisease AT kathrynbgarber pathogenicinframevariantsinscn8aexpandingthegeneticlandscapeofscn8aassociateddisease AT paulacgoldenberg pathogenicinframevariantsinscn8aexpandingthegeneticlandscapeofscn8aassociateddisease AT shobanakubendran pathogenicinframevariantsinscn8aexpandingthegeneticlandscapeofscn8aassociateddisease AT gbradleyschaefer pathogenicinframevariantsinscn8aexpandingthegeneticlandscapeofscn8aassociateddisease AT andrewescayg pathogenicinframevariantsinscn8aexpandingthegeneticlandscapeofscn8aassociateddisease
_version_	1718425902616936448

Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease

Ejemplares similares