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Cardiogenetics
Volume 1
Issue 1
10.4081/cardiogenetics.2011.e13
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Cardiogenetics is published by MDPI from Volume 10 Issue 2 (2020). Previous articles were published by another publisher in Open Access under a CC-BY (or CC-BY-NC-ND) licence, and they are hosted by MDPI on mdpi.com as a courtesy and upon agreement with PAGEPress.
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), 55-59; https://doi.org/10.4081/cardiogenetics.2011.e13
Received: 27 July 2011 / Revised: 18 October 2011 / Accepted: 21 October 2011 / Published: 25 October 2011
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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
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
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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, 55-59. 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):55-59. 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: 55-59. https://doi.org/10.4081/cardiogenetics.2011.e13

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