Abstract 12783: Analysis of SCN5A mutation and Antiarrhythmic Drug in Chinese Patients with Short QT Syndrome
Aims. We present, for the first time, that loss-of-function mutations in the SCN5A gene encoding for the strong depolarization channel Nav1.5 contribute to SQTS.
Methods and Results. We recruited nine probands having QTc ≤ 370 ms and no acquired causes of abbreviated QT interval. No mutations in previously known SQTS genes were identified in DNA screening of these individuals. However, two individuals were found to have one of the following heterozygous missense mutations in SCN5A: E428G (c.1283A>G) and V1951L (c.5851G>T). Both individuals displayed short QT intervals (QTc: 270 ms and 347 ms), a high predisposition to sudden cardiac death, and no underlying structural heart disease consistent with the robust phenotype of SQTS. A co-inherited synonymous polymorphism S1653S (c.4959C>A) in SCN5A was found in V1951L carriers. Whole-cell patch clamp analysis of HEK 293 cells expressing a mutated channel showed that E428G produced significant reduction of INa density, indicating a loss of function. INa in cells expressing V1951L or S1653S alone was not statistically different from that of wild-type (WT). However, co-expression of V1951L with S1653S in Nav1.5 produced a significant reduction of INa density, indicating a loss of function. The data suggest that the S1653S synonymous polymorphism has a noteworthy synergistic modulatory effect on the biophysical function of the L1951V mutation and acts as a genetic modifier of disease. The peak INa of the E428G channel in vitro was increased significantly in the presence of propafenone (30 µM), whereas there was no effect of amiodarone (50 µM) or mexiletine (50 µM),
Conclusion. This is the first study to show that loss-of-function mutations in the SCN5A gene contribute to SQTS and cause a new variant of SQTS. The synonymous polymorphism S1653S in the SCN5A gene significantly modifies the biophysical function of the L1951V mutation and causes loss of function in Nav1.5. Propafenone is a drug with the potential to treat SQTS caused by the E428G mutation.
- © 2012 by American Heart Association, Inc.