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

TLDR

Andersen syndrome is a rare inherited disorder marked by periodic paralysis, long QT with ventricular arrhythmias, and skeletal developmental abnormalities. The study aimed to characterize the functional consequences of KCNJ2 mutations and correlate them with clinical phenotypes, and to investigate arrhythmia mechanisms. Functional effects were assessed by two‑electrode voltage‑clamp of mutant Kir2.1 channels, and arrhythmia mechanisms were explored via ventricular myocyte modeling of reduced Kir2.1. All KCNJ2 mutations caused loss of function and dominant‑negative suppression, with 64 % of carriers experiencing periodic paralysis, 78 % dysmorphic features, 71 % long QT, and 64 % ventricular arrhythmias, yet none had sudden cardiac death; modeling revealed that reduced Kir2.1 prolongs the action‑potential terminal phase and induces Na⁺/Ca²⁺ exchanger–dependent delayed afterdepolarizations and spontaneous arrhythmias, indicating a distinct arrhythmia substrate from other inherited LQT syndromes.

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.