De novo BK channel variant causes epilepsy by affecting voltage gating but not Ca2+ sensitivity

Eur J Hum Genet. 2018 Feb;26(2):220-229. doi: 10.1038/s41431-017-0073-3.

Xia Li ¹, Sibylle Poschmann ², Qiuyun Chen ³ ⁴, Walid Fazeli ⁵, Nelly Jouayed Oundjian ⁶, Francesca M Snoeijen-Schouwenaars ⁷, Oliver Fricke ⁸, Erik-Jan Kamsteeg ⁹, Marjolein Willemsen ¹⁰ ¹¹, Qing Kenneth Wang ¹² ¹³ ¹⁴

Affiliations

1 Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
2 Children Hospital Dritter Orden, München, Germany.
3 Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Department of Cardiovascular Medicine, Cleveland Clinic, OH, USA.
4 Department of Genetics and Genome Science, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
5 University Children's Hospital Cologne, Pediatric Neurology, Cologne, Germany.
6 Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
7 Academic Department of Residential Care, Centre for Epileptology Kempenhaeghe, Heeze, The Netherlands.
8 Department of Child and Adolescent Psychiatry and Neuropediatrics, Gemeinschaftskrankenhaus Herdecke, Witten/Herdecke, Germany.
9 Department of Human Genetics, Radboud University Medical Center, HB Nijmegen, The Netherlands.
10 Department of Human Genetics, Radboud University Medical Center, HB Nijmegen, The Netherlands. [email protected].
11 Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands. [email protected].
12 Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China. [email protected].
13 Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Department of Cardiovascular Medicine, Cleveland Clinic, OH, USA. [email protected].
14 Department of Genetics and Genome Science, Case Western Reserve University School of Medicine, Cleveland, OH, USA. [email protected].

PMID: 29330545 DOI: 10.1038/s41431-017-0073-3

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.

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