Functional characterization of sodium channel mutations associated with epilepsy

• Grant number: 16/03896-3
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): April 01, 2016
• Effective date (End): May 31, 2021
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Iscia Teresinha Lopes Cendes
• Grantee: Demetrio Saul Lindo Samanamud
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 13/07559-3 - BRAINN - The Brazilian Institute of Neuroscience and Neurotechnology, AP.CEPID

Abstract

Nowadays, it is recognized that many epilepsy syndromes have an important genetic component, and several of these are monogenic. The SCN1A gene encodes the ±-subunit of the sodium channel voltage-dependent (Nav1.1). This channel is a multiprotein complex, whose function is to regulate the transport of sodium. Mutations in SCN1A deteriorate the control of the flux of sodium ions, and can result in abnormal sodium influx into neurons, disrupting channel activity and ultimately leading to neuronal hyperexcitability and epilepsy. Most patients with Dravet Syndrome (DS), a severe childhood epileptic encephalopathy, have de novo mutations in SCN1A. Indeed, previous studies by our group found that 81% of patients with DS have de novo mutations in SCN1A, most of which are missense. In addition, it has been described that mutations in SCN1A may be present in additional epilepsy syndromes, as well as other ion channel mutations may be present in patients with a variety of epilepsy syndromes. This poses additional problems in the interpretation of the photogenic impact of these mutations in protein function. Therefore, Nav1.1 functional studies (as well as of other ion channels) are important both to confirm results that were previously predicted exclusively by in silico analysis and to characterize mutations which could not be classified by bioinformatics tools. In this context, our main objective is to perform functional in vitro studies of mutated Nav1.1, as well as additional ion channels. We will introduce a variety of SCN1A variants, which have been previously identified, in our cohort of patients with DS and 3 in normal controls by using newly described genetic edition tools. In addition, we will perform a variety of biophysical measurements in order to characterize ion channel function. We expect that our results will not only help to improve molecular diagnosis of patients with DS and other epilepsies, but will also help us to better understand the repercussion of genetic variability (both normal and pathological) in the functional aspects of Nav1.1 sodium channels and other epilepsy-related ion channels. (AU)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

SAMANAMUD, Demetrio Saul Lindo. Construction and initial electrophysiological characterization of an in vitro system expressing the wild-type SCN1A gene and mutations associated with Dravet Syndrome. 2022. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas Campinas, SP.