De Novo Missense Variants of KCNA3, KCNA4, and KCNA6 Cause Early Onset Developmental Epileptic Encephalopathy
Abstract number :
2.327
Submission category :
12. Genetics / 12A. Human Studies
Year :
2022
Submission ID :
2204495
Source :
www.aesnet.org
Presentation date :
12/4/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:25 AM
Authors :
Meng-Han Tsai, MD, PhD – Kaohsiung Chang Gung Memorial Hospital; Chia-Hua Lo, Bs – National Yang Ming Chiao Tung University; Cheng-Yan Kuo, MD – Chang Gung Memorial Hospital; Yi-Hsuan Liu, MD – Chang Gung Memorial Hospital; Ying-Chao Chang, MD, PhD – Kaohsiung Chang Gung Memorial Hospital; Kuan-Lin Lin, MD – Chang Gung Memorial Hospital; Po-Chen Hung, MD – Chang Gung Memorial Hospital; Hwei-Hisen Chen, PhD – National Health Research Institute; Eric Hwang, PhD – National Yang Ming Chiao Tung University; Ya-Jean Wang, PhD – Minghsin University of Science and Technology
Rationale: Potassium (K+) channels are essential for the regulation of neuronal membrane potential and electrophysiological excitability. Half a dozen of potassium channel genes have been associated with human epilepsies, including two (KCNA1 and KCNA2) of the Shaker-type potassium channels (Kv1). The kv1 family contains 8 genes including 6 that were predominantly expressed in the CNS (Kv1.1-Kv1.6).
Methods: All patients were recruited at Chang Gung Memorial Hospital at Kaohsiung or Linko, underwent whole exome sequencing (WES) study. Identified variants were generated using site-directed mutagenesis and overexpressed in HEK293T cells using lentivirus. Electrophysiology using patch-clamp experiment was performed.
Results: We identified three patients with de novo missense pathogenic variants in three additional Shaker-type channel genes (KCNA3, KCNA4, and KCNA6). All variants were located in important functional domains such as the selectivity filter or the S6 hinge responsible for gating. Clinically, they presented as early-onset epileptic encephalopathy which subsided after the infantile period. Interestingly, the disease course coincides with the expression pattern of these genes. Electrophysiological studies confirmed loss of function effects in two of the variants, which could impair repolarization of the action potentials causing hyperexcitable neuronal activities.
Conclusions: Our findings expand the list of potassium channels genes, especially the Shaker-type, that cause human epilepsies.
Funding: This study is funded by Chang Gung Memorial Hospital, Ministry of Science and Technology, Taiwan and National Health Research Institute, Taiwan.
Genetics