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Cardiogenetics
Volume 1
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10.4081/cardiogenetics.2011.e13
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Article

LQTS-Associated Mutation A257G in α1-Syntrophin Interacts with the Intragenic Variant P74L to Modify Its Biophysical Phenotype

by
Jianding Cheng
1,2,
David W. Van Norstrand
3,
Argelia Medeiros-Domingo
3,4,
David J. Tester
3,4,
Carmen R. Valdivia
1,
Bi-Hua Tan
1,
Matteo Vatta
5,
Jonathan C. Makielski
1 and
Michael J. Ackerman
3,4,*
1
Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI, USA
2
Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
3
Department of Molecular Pharmacology & Experimental Therapeutics, Rochester, MN 55905, USA
4
Departments of Medicine and Pediatrics, Mayo Clinic, Rochester, MN, USA
5
Section of Pediatric Cardiology, Texas Children’s Hospital/Baylor College of Medicine, Houston, TX, USA
*
Author to whom correspondence should be addressed.
Cardiogenetics 2011, 1(1), e13; https://doi.org/10.4081/cardiogenetics.2011.e13
Submission received: 27 July 2011 / Revised: 18 October 2011 / Accepted: 21 October 2011 / Published: 25 October 2011

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

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MDPI and ACS Style

Cheng, J.; Van Norstrand, D.W.; Medeiros-Domingo, A.; Tester, D.J.; Valdivia, C.R.; Tan, B.-H.; Vatta, M.; Makielski, J.C.; Ackerman, M.J. LQTS-Associated Mutation A257G in α1-Syntrophin Interacts with the Intragenic Variant P74L to Modify Its Biophysical Phenotype. Cardiogenetics 2011, 1, e13. https://doi.org/10.4081/cardiogenetics.2011.e13

AMA Style

Cheng J, Van Norstrand DW, Medeiros-Domingo A, Tester DJ, Valdivia CR, Tan B-H, Vatta M, Makielski JC, Ackerman MJ. LQTS-Associated Mutation A257G in α1-Syntrophin Interacts with the Intragenic Variant P74L to Modify Its Biophysical Phenotype. Cardiogenetics. 2011; 1(1):e13. https://doi.org/10.4081/cardiogenetics.2011.e13

Chicago/Turabian Style

Cheng, Jianding, David W. Van Norstrand, Argelia Medeiros-Domingo, David J. Tester, Carmen R. Valdivia, Bi-Hua Tan, Matteo Vatta, Jonathan C. Makielski, and Michael J. Ackerman. 2011. "LQTS-Associated Mutation A257G in α1-Syntrophin Interacts with the Intragenic Variant P74L to Modify Its Biophysical Phenotype" Cardiogenetics 1, no. 1: e13. https://doi.org/10.4081/cardiogenetics.2011.e13

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