A novel Kir2.6 mutation associated with hypokalemic periodic paralysis

Clin Neurophysiol. 2016 Jun;127(6):2503-8. doi: 10.1016/j.clinph.2016.03.008. Epub 2016 Mar 17.


Background and objective: Mutations 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.

Methods: A 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.

Results: A 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%.

Conclusions: A 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.

Significance: This new G169R mutation of the potassium channel Kir2.6 provides insight into the pathogenic mechanisms of hypokalemic periodic paralysis.

Keywords: Gene mutation; Hypokalemic periodic paralysis; KCNJ18 gene; Kir2.6; Thyrotoxic periodic paralysis.

MeSH terms

  • Action Potentials
  • Adult
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • HEK293 Cells
  • Humans
  • Male
  • Mutation*
  • Paralysis, Hyperkalemic Periodic / genetics*
  • Potassium Channels, Inwardly Rectifying / genetics*


  • KCNJ18 protein, human
  • Potassium Channels, Inwardly Rectifying