Differential effects on sodium current impairments by distinct &ITSCN1A&IT mutations in GABAergic neurons derived from Dravet syndrome patients

Background: We investigated how two distinct mutations in SCN1A differentially affect electrophysiological properties of the patient-derived GABAergic neurons and clinical severities in two Dravet syndrome (DS) patients. Materials and Methods: We established induced pluripotent stem cells from two DS patients with different mutations in SCN1A and subsequently differentiated them into forebrain GABAergic neurons. Functionality of differentiated GABAergic neurons was examined by electrophysiological recordings. Results: DS-1 patient had a missense mutation, c.4261G > T [GenBank: NM 006920.4] and DS-2 patient had a nonsense frameshift mutation, c.3576_3580 del TCAAA [GenBank: NM 006920.4]. Clinically, contrary to our expectations, DS-1 patient had more severe symptoms including frequency of seizure episodes and the extent of intellectual ability penetration than DS-2 patient. Electrophysiologic recordings showed significantly lower sodium current density and reduced action potential frequency at strong current injection (>60 pA) in GABAergic neurons derived from both. Intriguingly, unique genetic alterations of SCN1A differentially impacted electrophysiological impairment of the neurons, and the impairment's extent corresponded with the symptomatic severity of the donor from which the iPSCs were derived. Conclusion: Our results suggest the possibility that patient-derived iPSCs may provide a reliable in vitro system that reflects clinical severities in individuals with DS. (C) 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.