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 alpha 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 Ca(2+) 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.
Background-Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and patients with AF have a significantly increased risk for ischemic stroke. Approximately 15% of all strokes are caused by AF. The molecular basis and underlying mechanisms and pathophysiology of AF remain largely unknown. Methods and Results-We have identified a large AF family with an autosomal recessive inheritance pattern. The AF in the family manifests with early onset at the fetal stage and is associated with neonatal sudden death and, in some cases, ventricular tachyarrhythmias and waxing and waning cardiomyopathy. Genome-wide linkage analysis was performed for 36 family members and generated a 2-point logarithm of the odds (LOD) score of 3.05 for marker D5S455. The maximum multipoint LOD score of 4.10 was obtained for 4 markers: D5S426, D5S493, D5S455, and D5S1998. Heterozygous carriers have significant prolongation of P-wave duration on ECGs compared with noncarriers (107 versus 85 ms on average; Pϭ0.000012), but no differences between these 2 groups were detected for the PR interval, QRS complex, ST-segment duration, T-wave duration, QTc, and R-R interval (PϾ0.05). Conclusions-Our findings demonstrate that AF can be inherited as an autosomal recessive trait and define a novel genetic locus for AF on chromosome 5p13 (arAF1). A genetic link between AF and prolonged P-wave duration was identified. This study provides a framework for the ultimate cloning of the arAF1 gene, which will increase the understanding of the fundamental molecular mechanisms of atrial fibrillation.
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