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. 2002 Aug;110(3):381-8.
doi: 10.1172/JCI15183.

Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome)

Martin Tristani-Firouzi  1 , Judy L Jensen, Matthew R Donaldson, Valeria Sansone, Giovanni Meola, Angelika Hahn, Said Bendahhou, Hubert Kwiecinski, Anna Fidzianska, Nikki Plaster, Ying-Hui Fu, Louis J Ptacek, Rabi Tawil
Affiliations

Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome)

Martin Tristani-Firouzi et al. J Clin Invest. 2002 Aug.

Abstract

Andersen syndrome (AS) is a rare, inherited disorder characterized by periodic paralysis, long QT (LQT) with ventricular arrhythmias, and skeletal developmental abnormalities. We recently established that AS is caused by mutations in KCNJ2, which encodes the inward rectifier K(+) channel Kir2.1. In this report, we characterized the functional consequences of three novel and seven previously described KCNJ2 mutations using a two-microelectrode voltage-clamp technique and correlated the findings with the clinical phenotype. All mutations resulted in loss of function and dominant-negative suppression of Kir2.1 channel function. In mutation carriers, the frequency of periodic paralysis was 64% and dysmorphic features 78%. LQT was the primary cardiac manifestation, present in 71% of KCNJ2 mutation carriers, with ventricular arrhythmias present in 64%. While arrhythmias were common, none of our subjects suffered sudden cardiac death. To gain insight into the mechanism of arrhythmia susceptibility, we simulated the effect of reduced Kir2.1 using a ventricular myocyte model. A reduction in Kir2.1 prolonged the terminal phase of the cardiac action potential, and in the setting of reduced extracellular K(+), induced Na(+)/Ca(2+) exchanger-dependent delayed afterdepolarizations and spontaneous arrhythmias. These findings suggest that the substrate for arrhythmia susceptibility in AS is distinct from the other forms of inherited LQT syndrome.

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Figures

Figure 1
Figure 1
Functional consequences of AS-associated mutations in KCNJ2. (a) Whole-cell currents in Xenopus oocytes induced by injection of WT KCNJ2, H2O, G144S and co-expressed WT and G144S KCNJ2. Currents were elicited by 200-ms pulses applied in 20-mV increments to potentials ranging from –150 to –10 mV from a holding potential of –70 mV. G144S mutant subunits failed to form functional channels when expressed alone. Coexpression of WT and G144S KCNJ2 induced small, inwardly rectifying currents. (b) Current voltage relationships for WT KCNJ2 (0.8 ng/oocyte) and coexpressed WT and mutant KCNJ2 (0.8 ng/oocyte of each cRNA). n = 10–18 oocytes/group. Inset, mean current between –70 and –30 mV shown on an expanded scale.
Figure 2
Figure 2
AS-associated mutations in KCNJ2 cause dominant-negative suppression of Kir2.1 channel function. (a) Peak current induced by coexpression of mutant and WT KCNJ2 (0.8 ng/oocyte for each) at –150 mV was normalized to currents induced by expression of WT KCNJ2 (0.8 ng/oocyte). Current magnitude is reported at –150 mV because this gives a measure of conductance in the absence of rectification. KCNJ2 mutations caused variable degrees of dominant-negative suppression of channel function. Note that a haploinsufficiency effect would result in current magnitude equal to that of the WT group. (b) Normalized current at –50 mV. KCNJ2 mutations also reduce magnitude of outward current in a dominant-negative manner. *D71V and R218W data were obtained from ref. .
Figure 3
Figure 3
Representative ECGs from AS subjects. (a) ECG demonstrating prolongation of the QT interval. (b) ECG traces demonstrating a short run of nonsustained polymorphic VT followed by bigeminy (normal QRS complex alternating with a premature ventricular complex). Ventricular arrhythmias dominated the rhythm of this subject throughout the day. (c) Bidirectional VT (note alternating QRS axis polarity) degenerating into a brief run of polymorphic VT. (d) ECG trace demonstrating prominent U wave (indicated by arrows).
Figure 4
Figure 4
ECG demonstrating bigeminy (sinus beat alternating with a PVC) in a 16-year-old female AS subject with hypokalemia. PVCs are indicated by asterisks. (b): Following an increase in serum K+, the bigeminy rhythm resolved. Six of 17 probands were documented to have exacerbation of ventricular ectopy in the setting of hypokalemia.
Figure 5
Figure 5
Simulated effect of reduced IK1 on cardiac action potentials. (a) Model of rabbit ventricular action potential under baseline conditions ([K+]O 4.5 meq/l, dashed line); 50% reduction in IK1 conductance (solid line); and 50% reduction in IK1 conductance and [K+]O = 2.9 meq/l (dotted line). (b) Reduction in [K+]O and IK1 conductance resulted in spontaneous action potentials (*) and DADs (**) that did not reach threshold for action potential generation. Basic cycle length of stimulation was 1,000 ms. (c) Spontaneous action potentials and DADs seen in b were eliminated by a reduction in the amplitude of the Na+/Ca2+ exchanger.
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