Analysis of SCN5A mutation and antiarrhythmic drug in Chinese Patients with Short QT Syndrome

• 作 者: Hui Zhou Kui Hong Su Juan Yan Jinzhu Hu Xiao Gang Peng Xiao Shu Cheng
• 机 构: The second affiliated hospital of Nanchang Univ,Nanchang of Jiangxi,China;Pedro Brugada,UZ Brussel-V
• 出 处: 中华医学会2012年医学遗传学年会暨全国第十一次医学遗传学学术会议
• 发表日期: 2012年8期

　　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 S 1653 S(c.4959C>A)in SCN5A was found in V 1951L 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 V 1951L or S 1653S alone was not statistically different from that of wild-type(WT).However,co-expression of V 1951L with S 1653 S in Nav 1.5 produced a significant reduction of INa density,indicating a loss of function.The data suggest that the S 1653S synonymous polymorphism has a noteworthy synergistic modulatory effect on the biophysical function of the L 1951V 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(30μm),whereas there was no effect of amiodarone(50μm)or mexiletine(50μm),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 S 1653S in the SCN5A gene significantly modifies the biophysical function of the L 1951V mutation and causes loss of function in Nav 1.5.Propafenone is a drug with the potential to treat SQTS caused by the E428G mutation.