Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder

• Published in: Nature genetics Vol. 37; no. 7; pp. 733 - 738
• Main Authors: Wang, Qing K, Du, Wei, Bautista, Jocelyn F, Yang, Huanghe, Diez-Sampedro, Ana, You, Sun-Ah, Wang, Lejin, Kotagal, Prakash, Lüders, Hans O, Shi, Jingyi, Cui, Jianmin, Richerson, George B
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.07.2005
• Subjects: Adolescent; Adult; Amino Acid Sequence; Animals; Base Sequence; Calcium; Child, Preschool; CHO Cells; Chorea - complications; Chorea - genetics; Chromosomes, Human, Pair 10; Conserved Sequence; Cricetinae; Cricetulus; Epilepsy; Epilepsy, Generalized - complications; Epilepsy, Generalized - genetics; Female; Genetic aspects; Humans; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Large-Conductance Calcium-Activated Potassium Channels; Molecular Sequence Data; Movement disorders; Mutation; Neurophysiology; Oocytes - physiology; Pedigree; Physiological aspects; Physiology; Potassium channels; Potassium Channels, Calcium-Activated - genetics; Potassium Channels, Calcium-Activated - physiology; Protein Subunits - genetics; Protein Subunits - physiology; Risk factors; Xenopus laevis; United States
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1585

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.