TY - JOUR
T1 - KCNJ2 mutations in arrhythmia patients referred for LQT testing
T2 - A mutation T305A with novel effect on rectification properties
AU - Eckhardt, Lee L.
AU - Farley, Amanda L.
AU - Rodriguez, Esther
AU - Ruwaldt, Karen
AU - Hammill, Daniel
AU - Tester, David J.
AU - Ackerman, Michael J.
AU - Makielski, Jonathan C.
N1 - Funding Information:
Comprehensive mutational analysis of KCNJ2 was performed using polymerase chain reaction (PCR), denaturing high performance liquid chromatography (DHPLC), and DNA sequencing. DNA amplification of the entire single exon coding region of the KCNJ2 gene was conducted using five overlapping fragments with PCR primers designed using Oligo Primer Analysis Software version 6.63 (Molecular Biology Insights, Inc., Cascade, Colorado) (primers, PCR and DHPLC conditions are available upon request). Control genomic DNA, comprised of 100 healthy white and 100 healthy black subjects, was obtained from the Human Genetic Cell Repository sponsored by the National Institute of General Medical Sciences and the Coriell Institute for Medical Research (Camden, New Jersey).
PY - 2007/3
Y1 - 2007/3
N2 - Background: Loss-of-function mutations in the KCNJ2 cause ∼50% of Andersen-Tawil Syndrome (ATS) characterized by a classic triad of periodic paralysis, ventricular arrhythmia, and dysmorphic features. Do KCNJ2 mutations occur in patients lacking this triad and lacking a family history of ATS? Objectives: The purpose of this study was to identify and characterize mutations in the KCNJ2-encoded inward rectifier potassium channel Kir2.1 from patients referred for genetic arrhythmia testing. Methods: Mutational analysis of KCNJ2 was performed for 541 unrelated patients. The mutations were made in wild type (WT) and expressed in COS-1 cells and voltage clamped for ion currents. Results: Three novel missense mutations (R67Q, R85W, and T305A) and one known mutation (T75M) were identified in 4/249 (1.6%) patients genotype-negative for other known arrhythmia genes with overall incidence 4/541 (0.74%). They had prominent U-waves, marked ventricular ectopy, and polymorphic ventricular tachycardia but no facial/skeletal abnormalities. Periodic paralysis was present in only one case. Outward current was decreased to less than 5% of WT for all mutants expressed alone. Co-expression with WT (simulating heterozygosity) caused a marked dominant negative effect for T75M and R82W, no dominant negative effect for R67Q, and a novel selective enhancement of inward rectification for T305A. Conclusions: KCNJ2 loss of function mutations were found in ∼1% of patients referred for genetic arrhythmia testing that lacked criteria for ATS. Characterization of three new mutations identified a novel dominant negative effect selectively reducing outward current for T305A. These results extend the range of clinical phenotype and molecular phenotype associated with KCNJ2 mutations.
AB - Background: Loss-of-function mutations in the KCNJ2 cause ∼50% of Andersen-Tawil Syndrome (ATS) characterized by a classic triad of periodic paralysis, ventricular arrhythmia, and dysmorphic features. Do KCNJ2 mutations occur in patients lacking this triad and lacking a family history of ATS? Objectives: The purpose of this study was to identify and characterize mutations in the KCNJ2-encoded inward rectifier potassium channel Kir2.1 from patients referred for genetic arrhythmia testing. Methods: Mutational analysis of KCNJ2 was performed for 541 unrelated patients. The mutations were made in wild type (WT) and expressed in COS-1 cells and voltage clamped for ion currents. Results: Three novel missense mutations (R67Q, R85W, and T305A) and one known mutation (T75M) were identified in 4/249 (1.6%) patients genotype-negative for other known arrhythmia genes with overall incidence 4/541 (0.74%). They had prominent U-waves, marked ventricular ectopy, and polymorphic ventricular tachycardia but no facial/skeletal abnormalities. Periodic paralysis was present in only one case. Outward current was decreased to less than 5% of WT for all mutants expressed alone. Co-expression with WT (simulating heterozygosity) caused a marked dominant negative effect for T75M and R82W, no dominant negative effect for R67Q, and a novel selective enhancement of inward rectification for T305A. Conclusions: KCNJ2 loss of function mutations were found in ∼1% of patients referred for genetic arrhythmia testing that lacked criteria for ATS. Characterization of three new mutations identified a novel dominant negative effect selectively reducing outward current for T305A. These results extend the range of clinical phenotype and molecular phenotype associated with KCNJ2 mutations.
KW - Gene expression
KW - Gene testing, Inward rectification, KIR2.1
KW - Ion channels
KW - K-channel
KW - Long QT syndrome
KW - Ventricular Arrhythmia
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U2 - 10.1016/j.hrthm.2006.10.025
DO - 10.1016/j.hrthm.2006.10.025
M3 - Article
C2 - 17341397
AN - SCOPUS:33847246042
SN - 1547-5271
VL - 4
SP - 323
EP - 329
JO - Heart rhythm
JF - Heart rhythm
IS - 3
ER -