BACKGROUND: Mutations in the SCN5A gene, encoding the α subunit of the cardiac Na(+) channel, Nav1.5, can result in several life-threatening arrhythmias. OBJECTIVE: To characterize a distal truncating SCN5A mutation, R1860Gfs*12, identified in a family with different phenotypes including sick sinus syndrome, atrial fibrillation (AF), atrial flutter, and atrioventricular block. METHODS: Patch-clamp and biochemical analyses were performed in human embryonic kidney 293 cells transfected with wild-type (WT) and/or mutant channels. RESULTS: The mutant channel expressed alone caused a 70% reduction in inward sodium current (INa) density compared to WT currents, which was consistent with its partial proteasomal degradation. It also led to a negative shift of steady-state inactivation and to a persistent current. When mimicking the heterozygous state of the patients by coexpressing WT and R1860Gfs*12 channels, the biophysical properties of INa were still altered and the mutant channel α subunits still interacted with the WT channels. Since the proband developed paroxysmal AF at a young age, we screened 17 polymorphisms associated with AF risk in this family and showed that the proband carries at-risk polymorphisms upstream of PITX2, a gene widely associated with AF development. In addition, when mimicking the difference in resting membrane potentials between cardiac atria and ventricles in human embryonic kidney 293 cells or when using computer model simulations, R1860Gfs*12 induced a more drastic decrease in INa at the atrial potential. CONCLUSION: We have identified a distal truncated SCN5A mutant associated with gain- and loss-of-function effects, leading to sick sinus syndrome and atrial arrhythmias. A constitutively higher susceptibility to arrhythmias of atrial tissues and genetic variability could explain the complex phenotype observed in this family.
BACKGROUND: Mutations in the SCN5A gene, encoding the α subunit of the cardiac Na(+) channel, Nav1.5, can result in several life-threatening arrhythmias. OBJECTIVE: To characterize a distal truncating SCN5A mutation, R1860Gfs*12, identified in a family with different phenotypes including sick sinus syndrome, atrial fibrillation (AF), atrial flutter, and atrioventricular block. METHODS: Patch-clamp and biochemical analyses were performed in humanembryonic kidney 293 cells transfected with wild-type (WT) and/or mutant channels. RESULTS: The mutant channel expressed alone caused a 70% reduction in inward sodium current (INa) density compared to WT currents, which was consistent with its partial proteasomal degradation. It also led to a negative shift of steady-state inactivation and to a persistent current. When mimicking the heterozygous state of the patients by coexpressing WT and R1860Gfs*12 channels, the biophysical properties of INa were still altered and the mutant channel α subunits still interacted with the WT channels. Since the proband developed paroxysmal AF at a young age, we screened 17 polymorphisms associated with AF risk in this family and showed that the proband carries at-risk polymorphisms upstream of PITX2, a gene widely associated with AF development. In addition, when mimicking the difference in resting membrane potentials between cardiac atria and ventricles in humanembryonic kidney 293 cells or when using computer model simulations, R1860Gfs*12 induced a more drastic decrease in INa at the atrial potential. CONCLUSION: We have identified a distal truncated SCN5A mutant associated with gain- and loss-of-function effects, leading to sick sinus syndrome and atrial arrhythmias. A constitutively higher susceptibility to arrhythmias of atrial tissues and genetic variability could explain the complex phenotype observed in this family.
Authors: Ming Lei; Catharine Goddard; Jie Liu; Anne-Laure Léoni; Anne Royer; Simon S-M Fung; Guosheng Xiao; Aiqun Ma; Henggui Zhang; Flavien Charpentier; Jamie I Vandenberg; William H Colledge; Andrew A Grace; Christopher L-H Huang Journal: J Physiol Date: 2005-06-02 Impact factor: 5.182
Authors: Jonathan N Johnson; David J Tester; James Perry; Benjamin A Salisbury; Carol R Reed; Michael J Ackerman Journal: Heart Rhythm Date: 2008-02-08 Impact factor: 6.343
Authors: Bi-Hua Tan; Pedro Iturralde-Torres; Argelia Medeiros-Domingo; Santiago Nava; David J Tester; Carmen R Valdivia; Teresa Tusié-Luna; Michael J Ackerman; Jonathan C Makielski Journal: Cardiovasc Res Date: 2007-08-22 Impact factor: 10.787
Authors: Alexander Burashnikov; José M Di Diego; Andrew C Zygmunt; Luiz Belardinelli; Charles Antzelevitch Journal: Circulation Date: 2007-09-04 Impact factor: 29.690
Authors: Daniel F Gudbjartsson; David O Arnar; Anna Helgadottir; Solveig Gretarsdottir; Hilma Holm; Asgeir Sigurdsson; Adalbjorg Jonasdottir; Adam Baker; Gudmar Thorleifsson; Kristleifur Kristjansson; Arnar Palsson; Thorarinn Blondal; Patrick Sulem; Valgerdur M Backman; Gudmundur A Hardarson; Ebba Palsdottir; Agnar Helgason; Runa Sigurjonsdottir; Jon T Sverrisson; Konstantinos Kostulas; Maggie C Y Ng; Larry Baum; Wing Yee So; Ka Sing Wong; Juliana C N Chan; Karen L Furie; Steven M Greenberg; Michelle Sale; Peter Kelly; Calum A MacRae; Eric E Smith; Jonathan Rosand; Jan Hillert; Ronald C W Ma; Patrick T Ellinor; Gudmundur Thorgeirsson; Jeffrey R Gulcher; Augustine Kong; Unnur Thorsteinsdottir; Kari Stefansson Journal: Nature Date: 2007-07-01 Impact factor: 49.962
Authors: Ivan Gando; Jace Morganstein; Kundan Jana; Thomas V McDonald; Yingying Tang; William A Coetzee Journal: Pacing Clin Electrophysiol Date: 2017-05-16 Impact factor: 1.976