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

• Published in: The Journal of clinical investigation 2002-08, Vol.110 (3), p.381-388
• Main Authors: Tristani-Firouzi, Martin, Jensen, Judy L, Donaldson, Matthew R, Sansone, Valeria, Meola, Giovanni, Hahn, Angelika, Bendahhou, Said, Kwiecinski, Hubert, Fidzianska, Anna, Plaster, Nikki, Fu, Ying-Hui, Ptacek, Louis J, Tawil, Rabi
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Animals; Arrhythmias, Cardiac; Biomedical research; Cardiac arrhythmia; Child; Electrophysiology; Female; Genotype & phenotype; Heart - physiopathology; Heart Defects, Congenital; Humans; Long QT Syndrome - genetics; Long QT Syndrome - physiopathology; Male; Middle Aged; Mutation; Paralyses, Familial Periodic - genetics; Paralyses, Familial Periodic - physiopathology; Potassium Channels, Inwardly Rectifying - genetics; Potassium Channels, Inwardly Rectifying - physiology; Rabbits; Syndrome
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI15183

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.