Affiliation:
1. From the Masonic Medical Research Laboratory (H.B.-M., D.H., G.O., G.C., M.D., E.B., C.A.), Utica, NY; and Fundacion para la Prevencion de la Muerte Subita-FEPREMUS and Centro de Estudios Geneticos (G.O., J.S.), Buenos Aires, Argentina.
Abstract
Background—
Mutations in
KCNJ2
, the gene encoding the human inward rectifier potassium channel Kir2.1 (I
K1
or I
Kir2.1
), have been identified in Andersen-Tawil syndrome. Andersen-Tawil syndrome is a multisystem inherited disease exhibiting periodic paralysis, cardiac arrhythmias, and dysmorphic features at times mimicking catecholaminergic polymorphic ventricular tachycardia.
Methods and Results—
Our proband displayed dysmorphic features including micrognathia, clinodactyly, and syndactyly and exhibited multiform extrasystoles and bidirectional ventricular tachycardia both at rest and during exercise testing. The patient's symptoms continued after administration of nadolol but subsided after treatment with flecainide. Molecular genetic screening revealed a novel heterozygous mutation (c.779G>C/p.R260P) in
KCNJ2
. Whole-cell patch-clamp studies conducted in TSA201 cells transfected with wild-type human
KCNJ2
cDNA (WT-
KCNJ2
) yielded robust I
Kir2.1
but no measurable current in cells expressing the R260P mutant. Coexpression of WT and R260P-
KCNJ2
(heterozygous expression) yielded a markedly reduced inward I
Kir2.1
compared with WT alone (−36.5±9.8 pA/pF versus −143.5±11.4 pA/pF, n=8 for both,
P
<0.001, respectively, at −90 mV), indicating a strong dominant negative effect of the mutant. The outward component of I
Kir2.1
measured at −50 mV was also markedly reduced with the heterozygous expression versus WT (0.52±5.5 pA/pF versus 23.4±6.7 pA/pF, n=8 for both,
P
<0.001, respectively). Immunocytochemical analysis indicates that impaired trafficking of R260P-
KCNJ2
channels.
Conclusions—
We report a novel de novo
KCNJ2
mutation associated with classic phenotypic features of Andersen-Tawil syndrome and catecholaminergic polymorphic ventricular tachycardia mimicry. The R260P mutation produces a strong dominant negative effect leading to marked suppression of I
K1
secondary to a trafficking defect.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Genetics(clinical),Cardiology and Cardiovascular Medicine,Genetics
Cited by
30 articles.
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