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

• Authors: Jennifer Wong, Emory University; Kameryn M Butler, Emory University; Lindsey Shapiro, Emory University; Jacquelyn T Thelin, Emory University; Kari A Mattison, Emory University; Kathryn Garber, Emory University; Paula C Goldenberg, Harvard Medical School; Shobana Kubendran, University of Kansas; Bradley G Schaefer, University of Arkansas Medical Sciences; Andrew Escayg, Emory University
• Journal Title: FRONTIERS IN PHARMACOLOGY
• Volume: Volume 12
• Publisher: FRONTIERS MEDIA SA | 2021-11-17, Pages 748415-748415
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.3389/fphar.2021.748415
• Subjects: Biology, Genetics; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Pharmacology & Pharmacy; SCN8A; sodium channel; epilepsy; seizure; mouse; mutation; SODIUM-CHANNEL SCN8A; DE-NOVO; EPILEPTIC ENCEPHALOPATHY; BINDING MOTIF; MUTATIONS; NA(V)1.6; SEIZURE; FAMILY; SCN1A; ACTIVATION

Abstract

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.