A novel Kir2.6 mutation associated with hypokalemic periodic paralysis

• A novel mutation of KCNJ18, G169R, was found to be associated with hypokalemic periodic paralysis with normal thyroid function.
• Functional characterization of this mutant Kir2.6 using patch clamp showed abnormally reduced inward and outward current densities.
• Findings extend previous knowledge on dysfunctions of Q126X, K360T, and E388K mutant Kir2.6 channels, which are associated with thyrotoxic periodic paralysis.

Background and objectiveMutations in KCNJ18, which encodes the inwardly rectifying potassium channel Kir2.6, have rarely been reported in hypokalemic periodic paralysis. We describe the clinical phenotype of a novel KCNJ18 gene mutation and perform functional characterization of this mutant Kir2.6.MethodsA long-term exercise test (ET) was conducted based on the McManis method. Whole-cell currents were recorded using patch clamp, and the HEK293 cells were transfected with wild-type or/and mutant Kir2.6 cDNA.ResultsA de novo conserved heterozygous mutation in Kir2.6, G169R, was found in a hypokalemic periodic paralysis patient. ET led to a decrease in the amplitude of compound muscle action potential (CMAP) by 64%. Patch clamp results showed that the potassium inward and outward current densities of the G169R mutant were, respectively, reduced by 65.6% and 84.7%; for co-expression with wild type, which more closely resembles the physiological conditions in vitro, the inward and outward current densities decreased, respectively, by 48.2% and 47.4%.ConclusionsA novel KCNJ18 mutation, G169R, was first reported to be associated with hypokalemic periodic paralysis without hyperthyroidism. Electrophysiological results demonstrated a significant functional defect of this mutant, which may predispose patients with this mutation to paralysis.SignificanceThis new G169R mutation of the potassium channel Kir2.6 provides insight into the pathogenic mechanisms of hypokalemic periodic paralysis.