Investigating the Role of R-type Channel Mutations in Developmental and Epileptic Encephalopathies
type: CreativeWork
description: Developmental and epileptic encephalopathies (DEEs) are a group of neurological disorders primarily affecting young children and are characterized by severe seizures. DEEs are challenging to manage and treat, with some patients experiencing severe side effects or not responding to frontline therapies. This is partly because of the many underlying mechanisms involved in DEE pathology and the relatively limited mechanism-specific action of frontline treatments. The majority of DEEs arise from genetic mutations, and one gene that has recently been implicated is CACNA1E, which encodes the voltage-gated calcium channel Cav2.3 (R-type). Mutations in CACNA1E have been identified in patients with DEEs; however, the mechanisms by which these mutations affect channel function, and thus their relationship to DEEs, remain largely unknown. Previous research has begun to characterize the functional effects of R-type channel mutations on channel biophysics, but only four mutations have been studied to date. With over 15 R-type channel mutations identified, further research is needed to functionally characterize additional mutants. To help address this gap, this study used whole-cell patch-clamping to examine the biophysics of two additional R-type channel mutants. The first mutant studied, R443W, showed no significant differences in channel biophysics compared with the wild-type (WT) R-type channel across most properties. However, this mutant channel showed more rapid calcium-dependent inactivation. The second mutant studied, L228P, exhibits a shift in window current toward more hyperpolarized voltages. Ultimately, these findings could help inform the development of novel therapies better suited to address the underlying molecular mechanism driving DEE pathology.
abstract: Developmental and epileptic encephalopathies (DEEs) are a group of neurological disorders primarily affecting young children and are characterized by severe seizures. DEEs are challenging to manage and treat, with some patients experiencing severe side effects or not responding to frontline therapies. This is partly because of the many underlying mechanisms involved in DEE pathology and the relatively limited mechanism-specific action of frontline treatments. The majority of DEEs arise from genetic mutations, and one gene that has recently been implicated is CACNA1E, which encodes the voltage-gated calcium channel Cav2.3 (R-type). Mutations in CACNA1E have been identified in patients with DEEs; however, the mechanisms by which these mutations affect channel function, and thus their relationship to DEEs, remain largely unknown. Previous research has begun to characterize the functional effects of R-type channel mutations on channel biophysics, but only four mutations have been studied to date. With over 15 R-type channel mutations identified, further research is needed to functionally characterize additional mutants. To help address this gap, this study used whole-cell patch-clamping to examine the biophysics of two additional R-type channel mutants. The first mutant studied, R443W, showed no significant differences in channel biophysics compared with the wild-type (WT) R-type channel across most properties. However, this mutant channel showed more rapid calcium-dependent inactivation. The second mutant studied, L228P, exhibits a shift in window current toward more hyperpolarized voltages. Ultimately, these findings could help inform the development of novel therapies better suited to address the underlying molecular mechanism driving DEE pathology.
author: Khousakoun, Devon
language: en
keywords: Voltage-gated calcium channels, Electrophysiology, Developmental and Epileptic Encephalopathies, Patch-clamp
date published: 2026-06-09
date modified: 2026-07-24T01:30:44Z
provider: University of Calgary
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Cumming School of Medicine

PropertyValue
property ID: Handle
value: https://hdl.handle.net/1880/125138

PropertyValue
property ID: DOI
value: 10.11575/PRISM/51562