Long QT syndrome (LQTS) is a familial autosomal dominant disease characterized by prolongation of the QT interval on the surface ECG, syncope, torsade de pointes and sudden cardiac death in young patients. Heritable LQTS is classified into different types (LQTS 1-12), and each type is linked to mutations in a specific gene. LQTS3 is associated with gain-of-function mutations in the SCN5A gene; the gene encodes the voltage-dependent cardiac sodium channel a-subunit that allows a large inward depolarizing current during phase 0 of the cardiac action potential. We identified and functionally characterized the novel SCN5A c.4416-4418delAAC (p.N1472del) mutation associated with LQTS. This deletion was engineered into the recombinant human heart sodium channel (hH1) and coexpressed with the human sodium channel ß-1 subunit (hß1) in the tsA201 cell line. The functional properties of the p.N1472del mutation were then determined by whole-cell patch clamp recording. The mutant channel had a decreased current density and the potential for half-maximal activation (V1/2) was shifted to more positive potential compared with wildtype (WT) channel; the slope factor (k) was higher in SCN5A-p.N1472del than in the WT channel. The mutant also exhibited a +12 mV depolarizing shift in the V1/2 of steady-state of inactivation compared with the WT, whereas WT and SCN5A-p.N1472del had similar slope factors. Moreover, the mutant had a slower recovery from inactivation experiments than WT. Finally, we tested if the mutant exhibited the increased persistent sodium current that is typical of SCN5A mutations associated with LQTS3. Current levels were persistently higher in SCN5Ap. N1472del than in the WT channel. In conclusion, our results demonstrate that p.N1472del mutation causes all the biophysical defects commonly associated with LQT (increased persistent current and positive shift in the voltage-dependence of inactivation) and is responsible for other functional alterations (positive shift in the voltage dependence of activation and a slower recovery from inactivation) which can be related to additional clinical defects.

The novel hh1 n1472del mutation in a long QT patient shows mixed biophysical properties / Detta, Nicola; Frisso, Giulia; A., Zullo; C., Cozzolino; B., Sarubbi; E., Romeo; D., Wang; R., Calabrò; Salvatore, Francesco; A. L., George. - STAMPA. - 34:(2010), pp. 426-426. (Intervento presentato al convegno 42° Congresso Nazionale SIBioC tenutosi a Roma nel 5-8 ottobre 2010).

The novel hh1 n1472del mutation in a long QT patient shows mixed biophysical properties

DETTA, NICOLA;FRISSO, GIULIA;SALVATORE, FRANCESCO;
2010

Abstract

Long QT syndrome (LQTS) is a familial autosomal dominant disease characterized by prolongation of the QT interval on the surface ECG, syncope, torsade de pointes and sudden cardiac death in young patients. Heritable LQTS is classified into different types (LQTS 1-12), and each type is linked to mutations in a specific gene. LQTS3 is associated with gain-of-function mutations in the SCN5A gene; the gene encodes the voltage-dependent cardiac sodium channel a-subunit that allows a large inward depolarizing current during phase 0 of the cardiac action potential. We identified and functionally characterized the novel SCN5A c.4416-4418delAAC (p.N1472del) mutation associated with LQTS. This deletion was engineered into the recombinant human heart sodium channel (hH1) and coexpressed with the human sodium channel ß-1 subunit (hß1) in the tsA201 cell line. The functional properties of the p.N1472del mutation were then determined by whole-cell patch clamp recording. The mutant channel had a decreased current density and the potential for half-maximal activation (V1/2) was shifted to more positive potential compared with wildtype (WT) channel; the slope factor (k) was higher in SCN5A-p.N1472del than in the WT channel. The mutant also exhibited a +12 mV depolarizing shift in the V1/2 of steady-state of inactivation compared with the WT, whereas WT and SCN5A-p.N1472del had similar slope factors. Moreover, the mutant had a slower recovery from inactivation experiments than WT. Finally, we tested if the mutant exhibited the increased persistent sodium current that is typical of SCN5A mutations associated with LQTS3. Current levels were persistently higher in SCN5Ap. N1472del than in the WT channel. In conclusion, our results demonstrate that p.N1472del mutation causes all the biophysical defects commonly associated with LQT (increased persistent current and positive shift in the voltage-dependence of inactivation) and is responsible for other functional alterations (positive shift in the voltage dependence of activation and a slower recovery from inactivation) which can be related to additional clinical defects.
2010
The novel hh1 n1472del mutation in a long QT patient shows mixed biophysical properties / Detta, Nicola; Frisso, Giulia; A., Zullo; C., Cozzolino; B., Sarubbi; E., Romeo; D., Wang; R., Calabrò; Salvatore, Francesco; A. L., George. - STAMPA. - 34:(2010), pp. 426-426. (Intervento presentato al convegno 42° Congresso Nazionale SIBioC tenutosi a Roma nel 5-8 ottobre 2010).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/407264
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