Wei Du1, 2, 9, Jocelyn F Bautista3, 4, 9, Huanghe Yang5, Ana Diez-Sampedro6, Sun-Ah You1, Lejin Wang1, Prakash Kotagal3, Hans O Lüders3, Jingyi Shi5, Jianmin Cui5, George B Richerson6, 7
& Qing K Wang1, 2, 81
Center for Molecular Genetics, Department of Molecular Cardiology, Lerner Research Institute; Center for Cardiovascular Genetics, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation; and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine; Case Western Reserve University; Cleveland; Ohio
44195; USA.
2
Department of Biological, Geological, and Environmental Science, Cleveland State University, Cleveland, Ohio
44115, USA.
3
Department of Neurology, The Cleveland Clinic Foundation, Cleveland, Ohio
44195, USA.
4
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio
44106, USA.
5
Department of Biomedical Engineering, Washington University, St. Louis, Missouri
63130, USA.
6
Departments of Neurology and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
06520, USA.
7
VAMC, West Haven, Connecticut
06516, USA.
8
Huazhong University of Science and Technology Human Genome Research Center, Wuhan, China.
9
These authors contributed equally to this work.
Correspondence should be addressed to Qing K Wang wangq2@ccf.org
subunit of the BK channel causes this syndrome. The mutant BK channel had a markedly greater macroscopic current. Single-channel recordings showed an increase in open-channel probability due to a three- to fivefold increase in Ca2+ sensitivity. We propose that enhancement of BK channels in vivo leads to increased excitability by inducing rapid repolarization of action potentials, resulting in generalized epilepsy and paroxysmal dyskinesia by allowing neurons to fire at a faster rate. These results identify a gene that is mutated in generalized epilepsy and paroxysmal dyskinesia and have implications for the pathogenesis of human epilepsy, the neurophysiology of paroxysmal movement disorders and the role of BK channels in neurological disease.
