SCN5A gene encodes for the α subunit of the cardiac isoform of the voltage gated sodium channel. Mutations in this gene have been correlated with several arrhytmogenic syndromes among which Long QT Syndrome (LQTS) type 3 and Brugada Syndrome (BrS) are the most studied. Here we describe two novel mutations related to these phenotypes. The c.86_87delinsTG causes the substitution of Ala 29 in the N-terminus of the protein with a Val and was found in a 36 years old man diagnosed with BrS. The mutation c.5089T>C substitute the Phe 1697 with a Ser in the intramembrane pore forming region and was found in a 45 years old woman diagnosed with LQTS. Whole cell patch-clamp studies on HEK293 cells revealed that both the mutations are responsible for a loss-of-function of the protein. In particular the A29V completely abolished the inward current. The F1697S mutation reduced the current density (-183.1±37.1 pA/pF, n=37 in WT vs -107.3±33.7 pA/pF, n=29 in F1697S; p<0.01) and caused a significant negative shift in the half-maximal voltage (V1/2) of steady- state inactivation curve and a positive one in the V1/2 of the activation curve (-8 and +6.4 mV, respectively). These gating changes caused a shift and a reduction in the window current that may markedly modify the action potential duration. Moreover, F1697S substitution slowed down the recovery from inactivation, being 8.1±0.2 ms (n=27) in WT and 12±0.4 ms (n=17) in F1697S the time necessary for the recovery of the 50% of the channels. These findings suggest that both the mutations strongly reduce the sodium inward current anticipating a higher risk of arrhythmogenesis for the patients. Still more has to be done in order to explain the clinical phenotype of LQTS in light of a loss-offunction of the F1697S Nav1.5 channel.

Murano, C., Binda, A., Lucano, D., Micaglio, E., Ciconte, G., Ghiroldi, A., et al. (2019). Two novel SCN5A loss-of-function mutations affect patients with severe arrhytmogenic syndromes. In Special Issue: Joint Meeting of the Federation of European Physiological Societies (FEPS) and the Italian Physiological Society (SIF) Bologna (Italy), September 10th – 13th 2019 (pp.22).

Two novel SCN5A loss-of-function mutations affect patients with severe arrhytmogenic syndromes

Murano C;Binda A;Rivolta I
2019

Abstract

SCN5A gene encodes for the α subunit of the cardiac isoform of the voltage gated sodium channel. Mutations in this gene have been correlated with several arrhytmogenic syndromes among which Long QT Syndrome (LQTS) type 3 and Brugada Syndrome (BrS) are the most studied. Here we describe two novel mutations related to these phenotypes. The c.86_87delinsTG causes the substitution of Ala 29 in the N-terminus of the protein with a Val and was found in a 36 years old man diagnosed with BrS. The mutation c.5089T>C substitute the Phe 1697 with a Ser in the intramembrane pore forming region and was found in a 45 years old woman diagnosed with LQTS. Whole cell patch-clamp studies on HEK293 cells revealed that both the mutations are responsible for a loss-of-function of the protein. In particular the A29V completely abolished the inward current. The F1697S mutation reduced the current density (-183.1±37.1 pA/pF, n=37 in WT vs -107.3±33.7 pA/pF, n=29 in F1697S; p<0.01) and caused a significant negative shift in the half-maximal voltage (V1/2) of steady- state inactivation curve and a positive one in the V1/2 of the activation curve (-8 and +6.4 mV, respectively). These gating changes caused a shift and a reduction in the window current that may markedly modify the action potential duration. Moreover, F1697S substitution slowed down the recovery from inactivation, being 8.1±0.2 ms (n=27) in WT and 12±0.4 ms (n=17) in F1697S the time necessary for the recovery of the 50% of the channels. These findings suggest that both the mutations strongly reduce the sodium inward current anticipating a higher risk of arrhythmogenesis for the patients. Still more has to be done in order to explain the clinical phenotype of LQTS in light of a loss-offunction of the F1697S Nav1.5 channel.
No
abstract
electrophysiology; cardiac disease; Brugada Syndrome
English
FEPS2019 - Federation of European Physiological Societies (FEPS) and the Italian Physiological Society (SIF)
2019
Murano, C., Binda, A., Lucano, D., Micaglio, E., Ciconte, G., Ghiroldi, A., et al. (2019). Two novel SCN5A loss-of-function mutations affect patients with severe arrhytmogenic syndromes. In Special Issue: Joint Meeting of the Federation of European Physiological Societies (FEPS) and the Italian Physiological Society (SIF) Bologna (Italy), September 10th – 13th 2019 (pp.22).
Murano, C; Binda, A; Lucano, D; Micaglio, E; Ciconte, G; Ghiroldi, A; Anastasia, L; Pappone, C; Rivolta, I
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/242387
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