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LQTS-associated mutation A257G in α1-syntrophin interacts with the intragenic variant P74L to modify its biophysical phenotype

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Author(s): Jianding Cheng | David W. Van Norstrand | Argelia Medeiros-Domingo | David J. Tester | Carmen R. Valdivia | Bi-Hua Tan | Matteo Vatta | Jonathan C. Makielski | Michael J. Ackerman

Journal: Cardiogenetics
ISSN 2035-8253

Volume: 1;
Issue: 1;
Start page: e13;
Date: 2011;
Original page

Keywords: long-QT syndrome | genetics | ion channels | SCN5A | syntrophin.

ABSTRACT
The SNTA1-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 overlapextension and were co-expressed heterologously with SCN5A in HEK293 cells. INa was recorded using the whole-cell method. Compared to wild-type (WT), the significant increase in peak INa and 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.
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