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

Numerous mutations have been identified, of which, the majority are 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 mutations exhibit seizures and a range of behaviora...

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Bibliographic Details
Published in:Frontiers in pharmacology 2021-11, Vol.12, p.748415-748415
Main Authors: Wong, Jennifer C, Butler, Kameryn M, Shapiro, Lindsey, Thelin, Jacquelyn T, Mattison, Kari A, Garber, Kathryn B, Goldenberg, Paula C, Kubendran, Shobana, Schaefer, G Bradley, Escayg, Andrew
Format: Article
Language:English
Subjects:
epilepsy
mouse
mutation
Pharmacology
SCN8A
seizure
sodium channel
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Summary:Numerous mutations have been identified, of which, the majority are 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 mutations exhibit seizures and a range of behavioral abnormalities. To date, there are only a few 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 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 deletion in the DIV S5-S6 pore region, highlighting the clinical relevance of this class of mutations.
ISSN:1663-9812
1663-9812
DOI:10.3389/fphar.2021.748415