Effects of a Novel Cav1.1-R1242G Mutation Leading to Hypokalemic Periodic Paralysis

Abstract

Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant muscle disorder characterized by attacks of flaccid weakness associated with a decrease in the serum potassium level. HypoPP is caused by mutations in the skeletal muscle calcium (Cav1.1)?1 or sodium (Nav1.4)? subunit. Up to date, 14 of 15 known HypoPP mutations affect the outmost two arginines in voltage-sensing S4 segments, suggesting the dysfunction of voltage sensor involved. A fresh perspective for HypoPP pathophysiology comes from the discovery of a hyperpolarization-induced inward gating pore current through the modified gating pore in Nav1.4 HypoPP mutations. The spectrum of HypoPP mutations has not been defined, so it remains to be determined whether the theory of the gating pore current could account for all cases of HypoPP. For Cav1.1 HypoPP mutations, the investigation is impeded by the difficulty of heterologous expression. Here, we describe an American family with a HypoPP type characterized by chronic progressive weakness whose affected members harbor a novel Cav1.1 R1242G mutation affecting the third arginine in S4 of domain IV. Whole-cell patch clamp recordings of the R1242G mutant showed a strong hyperpolarized shift of steady-state inactivation in GLT mouse myotube expression system. The facilitated inactivation resulting in the reduction of channel availability may account for the chronic progressive weakness of the patients. In addition, we found an outward gating pore current through the mutant voltage sensor of R1242G which might induce a reduction in the amplitude and duration of the action potential and cause the failure of muscle fiber excitability.