Universität zu Köln

Li, Xia, Poschmann, Sibylle, Chen, Qiuyun, Fazeli, Walid, Oundjian, Nelly Jouayed, Snoeijen-Schouwenaars, Francesca M., Fricke, Oliver, Kamsteeg, Erik-Jan, Willemsen, Marjolein and Wang, Qing Kenneth (2018). De novo BK channel variant causes epilepsy by affecting voltage gating but not Ca2+ sensitivity. Eur. J. Hum. Genet., 26 (2). S. 220 - 230. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5438

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Li, Xia UNSPECIFIED UNSPECIFIED UNSPECIFIED Poschmann, Sibylle UNSPECIFIED UNSPECIFIED UNSPECIFIED Chen, Qiuyun UNSPECIFIED UNSPECIFIED UNSPECIFIED Fazeli, Walid UNSPECIFIED UNSPECIFIED UNSPECIFIED Oundjian, Nelly Jouayed UNSPECIFIED UNSPECIFIED UNSPECIFIED Snoeijen-Schouwenaars, Francesca M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fricke, Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED Kamsteeg, Erik-Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Willemsen, Marjolein UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Qing Kenneth UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-197456
DOI:	10.1038/s41431-017-0073-3
Journal or Publication Title:	Eur. J. Hum. Genet.
Volume:	26
Number:	2
Page Range:	S. 220 - 230
Date:	2018
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5438
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHINESE GENEID POPULATION; ATRIAL-FIBRILLATION; LARGE-CONDUCTANCE; DENTATE GYRUS; K+ CHANNEL; IDENTIFICATION; ACTIVATION; PAXILLINE; NA(V)1.5; MUTATION Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19745