The investigation of pathophysiological mechanisms underlying KV7-related epilepsy and neurodevelopmental delay
type: CreativeWork
description: Affecting more than 65 million people worldwide, epilepsy is the fourth most common neurological disorder (Epilepsy Foundation). Neuronal Kv7 channels composed of Kv7.2/KCNQ2 and Kv7.3/KCNQ3 subunits are enriched at the axonal plasma membrane where their voltage-dependent potassium currents suppress neuronal excitability. Close to 400 variants in Kv7.2 subunit cause Benign Familial Neonatal Epilepsy (BFNE), Epileptic Encephalopathy (EE) and neurodevelopmental disorder (NDD). EE is often associated with poor response to antiepileptic drugs (AEDs), whereas both EE and NDD patients display progressive loss of cognitive and behavioral functions over time. While extensive studies have focused on BFNE mutations, the pathogenetic mechanism underlying EE and NDD variants in Kv7.2 remains unclear. The goal of this dissertation is to dissect the extent to which EE and NDD mutations in key functional domains affect the function, trafficking, expression, and regulation of Kv7.2 channels and how these changes impair their ability to control neuronal excitability and glutamate release. Chapter 2 presents our published study on the identification and characterization of EE mutation hotspots in Kv7.2 (Zhang, Kim, Chen et al., 2020, Scientific Reports). By combining statistical algorithm, electrophysiology, immunostaining and molecular dynamics simulation, our paper revealed that each EE mutation causes a unique combination of defects in Kv7 channel function, expression and regulation. Chapter 3 includes our submitted manuscript examining how PIP2 facilitates the voltage-dependent activation of Kv7.2 by strategically interacting with multiple clusters of basic residues in the voltage sensor, pore domain, and intracellular helices (Pant, Zhang, Kim et al., 2021, under revision at Communications Biology). Chapter 4 discusses my preliminary results and our lab’s future directions of a project investigating the underlying mechanism of EE and NDD variants in the S6 of Kv7.2. Chapter 5 co…
abstract: Affecting more than 65 million people worldwide, epilepsy is the fourth most common neurological disorder (Epilepsy Foundation). Neuronal Kv7 channels composed of Kv7.2/KCNQ2 and Kv7.3/KCNQ3 subunits are enriched at the axonal plasma membrane where their voltage-dependent potassium currents suppress neuronal excitability. Close to 400 variants in Kv7.2 subunit cause Benign Familial Neonatal Epilepsy (BFNE), Epileptic Encephalopathy (EE) and neurodevelopmental disorder (NDD). EE is often associated with poor response to antiepileptic drugs (AEDs), whereas both EE and NDD patients display progressive loss of cognitive and behavioral functions over time. While extensive studies have focused on BFNE mutations, the pathogenetic mechanism underlying EE and NDD variants in Kv7.2 remains unclear. The goal of this dissertation is to dissect the extent to which EE and NDD mutations in key functional domains affect the function, trafficking, expression, and regulation of Kv7.2 channels and how these changes impair their ability to control neuronal excitability and glutamate release. Chapter 2 presents our published study on the identification and characterization of EE mutation hotspots in Kv7.2 (Zhang, Kim, Chen et al., 2020, Scientific Reports). By combining statistical algorithm, electrophysiology, immunostaining and molecular dynamics simulation, our paper revealed that each EE mutation causes a unique combination of defects in Kv7 channel function, expression and regulation. Chapter 3 includes our submitted manuscript examining how PIP2 facilitates the voltage-dependent activation of Kv7.2 by strategically interacting with multiple clusters of basic residues in the voltage sensor, pore domain, and intracellular helices (Pant, Zhang, Kim et al., 2021, under revision at Communications Biology). Chapter 4 discusses my preliminary results and our lab’s future directions of a project investigating the underlying mechanism of EE and NDD variants in the S6 of Kv7.2. Chapter 5 co…
author: Zhang, Jiaren
language: en
keywords: Epilepsy, Ion channel, Epileptic encephalopathy, Kv7
date published: 2021-09-17T04:04:10Z
date modified: 2026-07-22T22:24:52Z
provider: University of Illinois - Urbana-Champaign
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Illinois at Urbana-Champaign

PropertyValue
property ID: Handle
value: http://hdl.handle.net/2142/110798