Abstract Title

Investigation of Hypokalemic Periodic Paralysis Mutation in a Voltage-Gated Sodium Channel

Presenter/Author/Faculty Mentor Information

Blake W. MartinFollow
James R. Groome (Mentor)Follow

Abstract

Patients with hypokalemic periodic paralysis type II experience flaccid paralysis coinciding with low serum potassium. This disease phenotype can be caused by mutations in hNaV1.4, a voltage-gated sodium channel (VGSC) found in human skeletal muscle. VGSC’s propagate vital electrical signals, called action potentials, in excitable cells such as these. While this disease is rare and usually not fatal, an understanding of the biophysical mechanisms underlying this channelopathy can provide extensive insight into the exact mechanism of function of VGSCs This particular study focused on the disease-causing point mutation, R222G, which replaces a positively charged amino acid, arginine, with a nonpolar glycine in a voltage sensing S4 segment. To study this mutated protein, PCR-based mutagenesis was used to create the point mutation in the SCN4A gene and mutated RNA was then inserted into Xenopus oocytes for expression. Cut-open voltage clamp electrophysiology was used to measure the probability of channel activation at a range of voltages. This data was then compared to that of the wild type data, allowing us to conclude that that the R222G mutation decreases the probability of activation. More experimentation is needed t before any concrete claims can be made.

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Investigation of Hypokalemic Periodic Paralysis Mutation in a Voltage-Gated Sodium Channel

Patients with hypokalemic periodic paralysis type II experience flaccid paralysis coinciding with low serum potassium. This disease phenotype can be caused by mutations in hNaV1.4, a voltage-gated sodium channel (VGSC) found in human skeletal muscle. VGSC’s propagate vital electrical signals, called action potentials, in excitable cells such as these. While this disease is rare and usually not fatal, an understanding of the biophysical mechanisms underlying this channelopathy can provide extensive insight into the exact mechanism of function of VGSCs This particular study focused on the disease-causing point mutation, R222G, which replaces a positively charged amino acid, arginine, with a nonpolar glycine in a voltage sensing S4 segment. To study this mutated protein, PCR-based mutagenesis was used to create the point mutation in the SCN4A gene and mutated RNA was then inserted into Xenopus oocytes for expression. Cut-open voltage clamp electrophysiology was used to measure the probability of channel activation at a range of voltages. This data was then compared to that of the wild type data, allowing us to conclude that that the R222G mutation decreases the probability of activation. More experimentation is needed t before any concrete claims can be made.