title: LQTS-associated mutation A257G in α1-syntrophin interacts with the intragenic variant P74L to modify its biophysical phenotype.
abstract: TheSNTA1-encoded α1-syntrophin (SNTA1) missense mutation, p.A257G, causes long QT syndrome (LQTS) by pathogenic accentuation of Nav1.5's sodium current (INa). Subsequently, we found p.A257G in combination with the SNTA1 polymorphism, p.P74L in 4 victims of sudden infant death syndrome (SIDS) as well as in 3 adult controls. We hypothesized that p.P74L-SNTA1 could functionally modify the pathogenic phenotype of p.A257G-SNTA1, thus explaining its occurrence in non-LQTS populations. The SNTA1 variants p.P74L, p.A257G, and the combination variant p.P74L/p.A257G were engineered using PCR-based overlap-extension and were co-expressed heterologously with SCN5A in HEK293 cells.INawas recorded using the whole-cell method. Compared to wild-type (WT), the significant increase in peakINaand window current found with p.A257G was reversed by the intragenic variant p.P74L (p.P74L/p.A257G). These results report for the first time the intragenic rescue of an LQT-associated SNTA1 mutation when found in combination with the SNTA1 polymorphism p.P74L, suggesting an ever-increasing picture of complexity in terms of genetic risk stratification for arrhythmia.
authors: Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI, USA ; Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors: Jianding
authors: J
authors: Cheng
authors: David W Van
authors: DW
authors: Norstrand
authors: Argelia
authors: A
authors: Medeiros-Domingo
authors: David J
authors: DJ
authors: Tester
authors: Carmen R
authors: CR
authors: Valdivia
authors: Bi-Hua
authors: BH
authors: Tan
authors: Matteo
authors: M
authors: Vatta
authors: Jonathan C
authors: JC
authors: Makielski
authors: Michael J
authors: MJ
authors: Ackerman
keywords: SCN5A; genetics; ion channels; long-QT syndrome; syntrophin