Electrophysiological characterization of a large set of novel variants in the SCN5A-gene: identification of novel LQTS3 and BrS mutations.
SCN5A encodes for the α-subunit of the cardiac voltage-gated sodium channel Nav1.5. Gain-of-function mutations in SCN5A are related to congenital long QT syndrome (LQTS3) characterized by delayed cardiac repolarization, leading to a prolonged QT interval in the ECG. Loss-of-function mutations in SCN5A are related to Brugada syndrome (BrS), characterized by an ST-segment elevation in the right precordial leads (V1-V3). The aim of this study was the characterization of a large set of novel SCN5A variants found in patients with different cardiac phenotypes, mainly LQTS and BrS. SCN5A variants of 13 families were functionally characterized in Xenopus laevis oocytes using the two-electrode voltage-clamp technique. We found in most of the cases, but not all, that the electrophysiology of the variants correlated with the clinically diagnosed phenotype. A susceptibility to develop LQTS can be suggested in patients carrying the variants S216L, K480N, A572D, F816Y, and G983D. However, taking the phenotype into account, the presence of the variants in genomic data bases, the mutational segregation, combined with our in vitro and in silico experiments, the variants S216L, S262G, K480N, A572D, F816Y, G983D, and T1526P remain as variants of unknown significance. However, the SCN5A variants R568H and A993T can be classified as pathogenic LQTS3 causing mutations, while R222stop and R2012H are novel BrS causing mutations.
Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstraße 1-2, 35037, Marburg, Germany.
Beatriz
B
Ortiz-Bonnin
Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstraße 1-2, 35037, Marburg, Germany.
Susanne
S
Rinné
Institute for Experimental Cardiovascular Medicine, University Heart Centre Freiburg - Bad Krozingen, Medical Center, University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Robin
R
Moss
Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstraße 1-2, 35037, Marburg, Germany.
Anne K
AK
Streit
Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstraße 1-2, 35037, Marburg, Germany.
Michael
M
Scharf
Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstraße 1-2, 35037, Marburg, Germany.
Katrin
K
Richter
Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstraße 1-2, 35037, Marburg, Germany.
Anika
A
Stöber
Helmholtz Zentrum München GmbH, Deutsches Forschungszentrum für Gesundheit und Umwelt, Institut für Humangenetik, Oberschleißheim, Germany.
Arne
A
Pfeufer
Institute for Experimental Cardiovascular Medicine, University Heart Centre Freiburg - Bad Krozingen, Medical Center, University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Gunnar
G
Seemann
Department of Medicine, University Hospital of the Ludwig Maximilians University-Campus Innenstadt and Großhadern, Munich, Germany.
Stefan
S
Kääb
Department of Medicine, University Hospital of the Ludwig Maximilians University-Campus Innenstadt and Großhadern, Munich, Germany.
Britt-Maria
BM
Beckmann
Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstraße 1-2, 35037, Marburg, Germany. decher@staff.uni-marburg.de.
Niels
N
Decher
D000328:Adult; D000818:Animals; D053840:Brugada Syndrome / Q000235:genetics; D000075224:Cardiac Conduction System Disease; D055724:Electrophysiological Phenomena / Q000235:genetics*; D006329:Heart Conduction System / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D009865:Oocytes / Q000378:metabolism; D010641:Phenotype; D014982:Xenopus laevis / Q000378:metabolism
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human
Brugada syndrome; LQT syndrome; Nav1.5; SCN5A; Sodium channel