A Novel Cav1.1-K1245Q Mutation Leading to Hypokalemic Periodic Paralysis

Abstract

Hypokalemic periodic paralysis (HypoPP) is the most common form of the periodic paralysis. It is caused by mutations in two voltage-gated ion channels of skeletal muscle, Cav1.1 (HypoPP-1) and Nav1.4 (HypoPP-2). Almost all HypoPP-causing mutations replace positive amino acids in the S4 voltage sensor of the channels. S4 mutations in Nav1.4 channels have already been shown to conduct sodium or protons through the omega pore which cause depolarization and impair the action potential generation. A leak current conducted by muscle fibers from HypoPP-1 patients was shown; however it was not formally demonstrated to be conducted by an omega pore. A novel mutation K1245Q in S4 of domain IV of Cav1.1 was identified in a patient who expressed weakness attacks with low serum potassium suggestive of HypoPP. These attacks have also been provoked by carbohydrate application. Further investigations revealed this mutation in other affected family members. To investigate possible gating alterations in the Cav1.1-K1245Q mutation, we performed whole-cell patch clamp measurements. A GLT cell line from muscular dysgenic mice (mdg) was cultured and transiently transfected with cDNA of wild type (WT) or mutant (K1245Q) Cav1.1. Calcium current amplitudes and voltage dependencies of activation of WT and K1245Q did not show significant differences in absolute or relative values. This data does not explain the patients pathogenesis. Omega currents produced by HypoPP Nav1.4 mutations might also exist in this Cav1.1-K1245Q mutant which could contribute to the phenotype of the patients. The corresponding measurements are currently performed, the results will be presented.