@article{a414b7be18d841aab53c9fef6a51b1d3,
title = "Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder",
abstract = "The large conductance calcium-sensitive potassium (BK) channel is widely expressed in many organs and tissues, but its in vivo physiological functions have not been fully defined. Here we report a genetic locus associated with a human syndrome of coexistent generalized epilepsy and paroxysmal dyskinesia on chromosome 10q22 and show that a mutation of the α 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.",
author = "Wei Du and Bautista, {Jocelyn F.} and Huanghe Yang and Ana Diez-Sampedro and You, {Sun Ah} and Lejin Wang and Prakash Kotagal and L{\"u}ders, {Hans O.} and Jingyi Shi and Jianmin Cui and Richerson, {George B.} and Wang, {Qing K.}",
note = "Funding Information: We thank I.B. Levitan, Y. Zhou, L. Salkoff and A. Butler for the expression constructs for KCNMA1; the study participants for their enthusiasm for and support of this study; L. Li for lod score calculation; S. Yong, G. Kirsch, C.J. Lingle, T. Zhang, A. Alexopoulos and I. Najm for help and discussion; and R. Guerrini for providing DNA from two individuals with epilepsy and paroxysmal dyskinesia3 (no KCNMA1 mutation was identified in these two DNA samples). This work was supported by grants from the US National Institutes of Health (Q.K.W., J.F.B., G.B.R. & A.D.-S. and J.C.), an American Heart Association Established Investigator award (Q.K.W.), the VAMC (G.B.R.) and a Clinical Research Training Fellowship from the American Academy of Neurology Foundation (J.F.B.). This work was supported in part by the Chinese Ministry of Science and Technology National High Technology 863 Project grant (Q.K.W.) and a Public Health Service National Center for Research Resources grant at the Cleveland Clinic Foundation (Q.K.W.).",
year = "2005",
doi = "10.1038/ng1585",
language = "English",
volume = "37",
pages = "733--738",
journal = "Nature Genetics",
issn = "1061-4036",
number = "7",
}