Investigating the Role of R-type Channel Mutations in Developmental and Epileptic Encephalopathies

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.

Name thesis:degree_name

Master of Science (MSc)

Discipline thesis:degree_discipline

Medicine – Neuroscience

Grantor

Cumming School of Medicine

Year dc:date.issued

2026

Author dc:creator

• Khousakoun, Devon

Advisor dc:contributor.advisor

• Zamponi, Gerald

Committee members dc:contributor.committeemember

• Chen, Wayne
• Scantlebury, Morris

• Voltage-gated calcium channels
• Electrophysiology
• Developmental and Epileptic Encephalopathies
• Patch-clamp

Statement dc:rights

• Unless otherwise indicated, this material is protected by copyright and has been made available with authorization from the copyright owner. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.

Language dc:language.iso

en

DOI

https://dx.doi.org/10.11575/PRISM/51562

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:1880/125138