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

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+/Ca2+ 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

Management and Treatment of Andersen-Tawil Syndrome (ATS)

“…The identification of the gene led to the classification of ATS as an LQT (LQT7) syndrome in the cardiology literature. Tristani-Firouzi et al 6 subsequently characterized the functional and clinical consequences of KCNJ2 mutations associated with ATS. LQT occurs in 50% of patients with ATS.…”

“…Other mutations act by a mechanism of haploinsufficiency, probably affecting trafficking and assembly of second messengers via the interaction of abnormal amino acid positioning along the muscle membrane where the Kir2.1 channels are localized. 6,[22][23][24] Given the ubiquitous distribution of Kir2.1 channels and the complexity of their interactions with second messengers and other associated membrane components, including anchoring and modeling molecules, it would not be surprising that the effects on these channels would extend to other molecular targets affecting other tissues or organs, either directly or indirectly. It is likely, therefore, that a wider spectrum of phenotypic expressions of KCNJ2 mutations exists.…”

“…The complex and frequent ventricular ectopy rarely degenerates into lifethreatening ventricular tachyarrhythmias and sudden death is less frequent in ATS than in other LQT syndromes. [5][6][7]12 What ECG features, if any, predict the occurrence of symptomatic or life-threatening arrhythmias remains to be determined.…”

“…Recently, ATS has been linked to mutations in the KCNJ2 gene which codes for a voltagegated, inward rectifying potassium channel (Kir2.1). 5,6 The majority of ATS patients described so far (80%-90%) have a KCNJ2 mutation, causing paralysis and cardiac arrhythmias through a dominant-negative effect of the mutation on potassium current (ATS1). Less clear is the way these mutations account for facial and skeletal abnormalities and whether there are other clinical manifestations of ATS given the ubiquitous distribution of Kir2.1 channels.…”

Cellular basis for electrocardiographic and arrhythmic manifestations of Andersen-Tawil syndrome (LQT7)

“…[1][2][3][4][5][6] This skeletal muscle syndrome is associated with periodic paralysis often linked to fluctuations in plasma potassium levels. 2,7,8 Clinical studies indicate that Andersen-Tawil syndrome may be associated with arrhythmias, particularly when aggravated by other health problems such as infection. 3 The cellular basis for the ECG and arrhythmogenic manifestations of Andersen-Tawil syndrome are not well defined.…”