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.

Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome) / M. Tristani-Firouzi, J.L. Jensen, M.R. Donaldson, V. Sansone, G. Meola, A. Hahn, S. Bendahhou, H. Kwiecinski, A. Fidzianska, N. Plaster, Y.H. Fu, L.J. Ptacek, R. Tawil. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 0021-9738. - 110:3(2002 Aug), pp. 381-388. [10.1172/JCI15183]

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

V. Sansone;G. Meola;
2002

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.
Settore MED/26 - Neurologia
ago-2002
Article (author)
File in questo prodotto:
File Dimensione Formato  
J CLIN INVEST 2002- Tristani-Firouzi M.pdf

accesso solo dalla rete interna

Tipologia: Pre-print (manoscritto inviato all'editore)
Dimensione 676.4 kB
Formato Adobe PDF
676.4 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/210098
Citazioni
  • ???jsp.display-item.citation.pmc??? 125
  • Scopus 479
  • ???jsp.display-item.citation.isi??? 369
social impact