HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

KCNJ2 mutation causes an adrenergic-dependent rectification abnormality with calcium sensitivity and ventricular arrhythmia.

AbstractBACKGROUND:
KCNJ2 mutations are associated with a variety of inherited arrhythmia syndromes including catecholaminergic polymorphic ventricular tachycardia 3.
OBJECTIVE:
To characterize the detailed cellular mechanisms of the clinically recognized KCNJ2 mutation R67Q.
METHODS:
Kir2.1 current density was measured from COS-1 cells transiently transfected with wild-type human Kir-2.1 (WT-Kir2.1) and/or a heterozygous missense mutation in KCNJ2 (R67Q-Kir2.1) by using the whole-cell voltage clamp technique. Catecholamine activity was simulated with protein kinase A-stimulating cocktail exposure. Phosphorylation-deficient mutants, S425N-Kir2.1 and S425N-Kir2.1/R67Q-S425N-Kir2.1, were used in a separate set of experiments. HA- or Myc-Tag-WT-Kir2.1 and HA-Tag-R67Q-Kir2.1 were used for confocal imaging.
RESULTS:
A 33-year-old woman presented with a catecholaminergic polymorphic ventricular tachycardia-like clinical phenotype and was found to have KCNJ2 missense mutation R67Q. Treatment with nadolol and flecainide resulted in the complete suppression of arrhythmias and symptom resolution. Under baseline conditions, R67Q-Kir2.1 expressed alone did not produce inward rectifier current while cells coexpressing WT-Kir2.1 and R67Q-Kir2.1 demonstrated the rectification index (RI) similar to that of WT-Kir2.1. After PKA stimulation, R67Q-Kir2.1/WT-Kir2.1 failed to increase peak outward current density; WT-Kir2.1 increased by 46% (n = 5), while R67Q-Kir2.1/WT-Kir2.1 decreased by 6% (n = 6) (P = .002). Rectification properties in R67Q-Kir2.1/WT-Kir2.1 demonstrated sensitivity to calcium with a decreased RI in the high-calcium pipette solution (RI 20.3% ± 4.1%) than in the low-calcium pipette solution (RI 36.5% ± 5.7%) (P < .05). Immunostaining of WT-Kir2.1 and R67Q-Kir2.1 individually and together showed a normal membrane expression pattern and colocalization by using the Pearson correlation coefficient.
CONCLUSIONS:
R67Q-Kir2.1 is associated with an adrenergic-dependent clinical and cellular phenotype with rectification abnormality enhanced by increased calcium. These findings are a significant advancement of our knowledge and understanding of the phenotype-genotype relationship of arrhythmia syndromes related to KCNJ2 mutations.
AuthorsMatthew M Kalscheur, Ravi Vaidyanathan, Kate M Orland, Sara Abozeid, Nicholas Fabry, Kathleen R Maginot, Craig T January, Jonathan C Makielski, Lee L Eckhardt
JournalHeart rhythm (Heart Rhythm) Vol. 11 Issue 5 Pg. 885-94 (May 2014) ISSN: 1556-3871 [Electronic] United States
PMID24561538 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Kir2.1 channel
  • Potassium Channels, Inwardly Rectifying
  • DNA
  • Calcium
Topics
  • Adult
  • Calcium (metabolism)
  • DNA (genetics)
  • DNA Mutational Analysis
  • Female
  • Genetic Predisposition to Disease
  • Heterozygote
  • Humans
  • Mutation, Missense
  • Patch-Clamp Techniques
  • Potassium Channels, Inwardly Rectifying (genetics, metabolism)
  • Tachycardia, Ventricular (genetics, metabolism, physiopathology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: