AUTHOR=Mao Xiao , Bruneau Nadine , Gao Quwen , Becq Hélène , Jia Zhengjun , Xi Hui , Shu Li , Wang Hua , Szepetowski Pierre , Aniksztejn Laurent 

TITLE=The Epilepsy of Infancy With Migrating Focal Seizures: Identification of de novo Mutations of the KCNT2 Gene That Exert Inhibitory Effects on the Corresponding Heteromeric KNa1.1/KNa1.2 Potassium Channel

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=14

YEAR=2020

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2020.00001

DOI=10.3389/fncel.2020.00001

ISSN=1662-5102

ABSTRACT=<p>The epilepsy of infancy with migrating focal seizures (EIMFS; previously called Malignant migrating partial seizures of infancy) are early-onset epileptic encephalopathies (EOEE) that associate multifocal ictal discharges and profound psychomotor retardation. EIMFS have a genetic origin and are mostly caused by <italic>de novo</italic> mutations in the <italic>KCNT1</italic> gene, and much more rarely in the <italic>KCNT2</italic> gene. <italic>KCNT1</italic> and <italic>KCNT2</italic> respectively encode the K<sub>Na</sub>1.1 (Slack) and K<sub>Na</sub>1.2 (Slick) subunits of the sodium-dependent voltage-gated potassium channel K<sub>Na</sub>. Functional analyses of the corresponding mutant homomeric channels <italic>in vitro</italic> suggested gain-of-function effects. Here, we report two novel, <italic>de novo</italic> truncating mutations of <italic>KCNT2</italic>: one mutation is frameshift (p.L48Qfs43), is situated in the N-terminal domain, and was found in a patient with EOEE (possibly EIMFS); the other mutation is nonsense (p.K564*), is located in the C-terminal region, and was found in a typical EIMFS patient. Using whole-cell patch-clamp recordings, we have analyzed the functional consequences of those two novel <italic>KCNT2</italic> mutations on reconstituted K<sub>Na</sub>1.2 homomeric and K<sub>Na</sub>1.1/K<sub>Na</sub>1.2 heteromeric channels in transfected chinese hamster ovary (CHO) cells. We report that both mutations significantly impacted on K<sub>Na</sub> function; notably, they decreased the global current density of heteromeric channels by ~25% (p.K564*) and ~55% (p.L48Qfs43). Overall our data emphasize the involvement of <italic>KCNT2</italic> in EOEE and provide novel insights into the role of heteromeric K<sub>Na</sub> channel in the severe <italic>KCNT2</italic>-related epileptic phenotypes. This may have important implications regarding the elaboration of future treatment.</p>