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LQTS-Associated Mutation A257G in Alpha1-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: 2;
Date: 2011;
Original page

Keywords: Long-QT syndrome | genetics | ion channels | SCN5A | syntrophin

ABSTRACT
Background: The SNTA1-encoded a1-syntrophin (SNTA1) missense mutation, A257G, causes long QT syndrome (LQTS) by pathogenic accentuation of Nav1.5’s sodium current (INa). Subsequently, we found A257G in combination with a common SNTA1 polymorphism, P74L in 4 victims of sudden infant death syndrome (SIDS) as well as in 3 adult controls. We hypothesized that P74L-SNTA1 could functionally modify the pathogenic phenotype of A257G-SNTA1, thus explaining its occurrence in non-LQTS populations.Design and Methods: The SNTA1 variants P74L, A257G, and P74L/A257G were engineered using PCR-based overlap-extension and were co-expressed heterologously with SCN5A in HEK293 cells. INa was recorded using the whole-cell method.Results: Compared to wild-type (WT), the significant increase in peak INa and window current found with A257G was reversed by the intragenic variant P74L (P74L/A257G).Conclusions: These results report for the first time the intragenic rescue of an LQT-associated SNTA1 mutation when found in combination with a common SNTA1 polymorphism, suggesting an ever-increasing picture of complexity in terms of genetic risk stratification for arrhythmia.
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