De novo BK channel variant causes epilepsy by affecting voltage gating but not Ca 2+ sensitivity

Epilepsy is one of the most common neurological diseases and it causes profound morbidity and mortality. We identified the first de novo variant in KCNMA1 (c.2984 A > G (p.(N995S)))-encoding the BK channel-that causes epilepsy, but not paroxysmal dyskinesia, in two independent families. The c.298...

Full description

Saved in:
Bibliographic Details
Published in:European journal of human genetics : EJHG 2018-02, Vol.26 (2), p.220
Main Authors: Li, Xia, Poschmann, Sibylle, Chen, Qiuyun, Fazeli, Walid, Oundjian, Nelly Jouayed, Snoeijen-Schouwenaars, Francesca M, Fricke, Oliver, Kamsteeg, Erik-Jan, Willemsen, Marjolein, Wang, Qing Kenneth
Format: Article
Language:English
Subjects:
Calcium - metabolism
Child
Child, Preschool
Epilepsy - genetics
Epilepsy - pathology
Female
HEK293 Cells
Humans
Ion Channel Gating
Large-Conductance Calcium-Activated Potassium Channel alpha Subunits - genetics
Large-Conductance Calcium-Activated Potassium Channel alpha Subunits - metabolism
Male
Mutation
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Epilepsy is one of the most common neurological diseases and it causes profound morbidity and mortality. We identified the first de novo variant in KCNMA1 (c.2984 A > G (p.(N995S)))-encoding the BK channel-that causes epilepsy, but not paroxysmal dyskinesia, in two independent families. The c.2984 A > G (p.(N995S)) variant markedly increased the macroscopic potassium current by increasing both the channel open probability and channel open dwell time. The c.2984 A > G (p.(N995S)) variant did not affect the calcium sensitivity of the channel. We also identified three other variants of unknown significance (c.1554 G > T (p.(K518N)), c.1967A > C (p.(E656A)), and c.3476 A > G (p.(N1159S))) in three separate patients with divergent epileptic phenotypes. However, these variants did not affect the BK potassium current, and are therefore unlikely to be disease-causing. These results demonstrate that BK channel variants can cause epilepsy without paroxysmal dyskinesia. The underlying molecular mechanism can be increased activation of the BK channel by increased sensitivity to the voltage-dependent activation without affecting the sensitivity to the calcium-dependent activation. Our data suggest that the BK channel may represent a drug target for the treatment of epilepsy. Our data highlight the importance of functional electrophysiological studies of BK channel variants in distinguishing whether a genomic variant of unknown significance is a disease-causing variant or a benign variant.
ISSN:1476-5438