A common SCN5A polymorphism modulates the biophysical defects of SCN5A mutations.
BACKGROUND
Defects in the cardiac sodium channel gene, SCN5A, can cause a broad spectrum of inherited arrhythmia syndromes. After genotyping of a proband who presented with syncope, the SCN5A mutant P2006A and the common polymorphism H558R were identified.


OBJECTIVE
The main objective of this study was to determine whether the SCN5A-H558R polymorphism could modify the defective gating kinetics observed in the P2006A mutation and therefore explain why this gain-of-function mutation has been identified in control populations.


METHODS
Mutations were engineered using site-directed mutagenesis and heterologously expressed transiently in HEK293 cells. Whole-cell sodium currents were measured at room temperature using the whole-cell patch-clamp technique.


RESULTS
In HEK293 cells, P2006A displayed biophysical defects typically associated with long QT syndrome by increasing persistent sodium current, producing a depolarizing shift in voltage dependence of inactivation, and hastening recovery from inactivation. Interestingly, when coexpressed either on the same or different genes, P2006A and H558R displayed currents that behaved like wild type (WT). We also investigated whether H558R can modulate the gating defects of other SCN5A mutations. The H558R polymorphism also restored the gating defects of the SCN5A mutation V1951L to the WT level.


CONCLUSIONS
Our results suggest that H558R might play an important role in stabilization of channel fast inactivation and may provide a plausible explanation as to why the P2006A gain-of-function mutation has been identified in control populations. Our results also suggest that the SCN5A polymorphism H558R might be a disease-modifying gene.
Heart and Vascular Research Center, Department of Medicine, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio 44109-1998, USA.
Krekwit
K
Shinlapawittayatorn
Xi X
XX
Du
Haiyan
H
Liu
Eckhard
E
Ficker
Elizabeth S
ES
Kaufman
Isabelle
I
Deschênes
D000293:Adolescent; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics; D008133:Long QT Syndrome / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015222:Sodium Channels / Q000235:genetics*
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels