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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Acknowledgements
We are grateful to Dr. Johannes Lemke for help and assistance and Dr. Jiuping Ding for the gift of the expression construct for KCNMA1 and KCNMB4. We thank Chengcheng Tan and Hongbo Xiong for help and assistance. This work was supported by the China National Natural Science Foundation grants (31430047, 81630002, and 91439129), 2016 Top-Notch Innovative Talent Development Project from the Bureau of Human Resources, and Social Security of Wuhan City, Chinese National Basic Research Programs (973 Programs 2013CB531101), Hubei Province Natural Science Key Program (2014CFA074), and NIH/NHLBI grants R01 HL121358 and R01 HL126729.
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Xia Li, Sibylle Poschmann, Qiuyun Chen, and Walid Fazeli contributed equally to this work.
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Li, X., Poschmann, S., Chen, Q. et al. De novo BK channel variant causes epilepsy by affecting voltage gating but not Ca2+ sensitivity. Eur J Hum Genet 26, 220–229 (2018). https://doi.org/10.1038/s41431-017-0073-3
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DOI: https://doi.org/10.1038/s41431-017-0073-3
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