LQTS-associated mutation A257G in α1-syntrophin interacts with the intragenic variant P74L to modify its biophysical phenotype
AbstractThe 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.
Schwartz PJ, Crotti L. Ion channel diseases in children: manifestations and management. Curr Opin Cardiol 2008;23:184-91.
Ackerman MJ. The long QT syndrome: ion channel diseases of the heart. Mayo Clin Proc 1998;73:250-69.
Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000;102:1178-85.
Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm 2005;2:507-17.
Wang Q, Curran ME, Splawski I, et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 1996;12:17-23.
Curran ME, Splawski I, Timothy KW, et al. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995;80:795-803.
Wang Q, Shen J, Splawski I, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805-11.
Schwartz PJ, Stramba-Badiale M, Segantini A, et al. Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med 1998;338:1709-14.
Schwartz PJ, Priori SG, Dumaine R, et al. A molecular link between the sudden infant death syndrome and the long- QT syndrome. N Engl J Med 2000;343:262-7.
Brugada R, Hong K, Dumaine R, et al. Sudden death associated with short-QT syndrome linked mutations in HERG. Circulation 2004;109:30-5.
Tester DJ, Ackerman MJ. Sudden infant death syndrome: how significant are the cardiac channelopathies? Cardiovasc Res 2005;67:388-96.
Arnestad M, Crotti L, Rognum TO, et al. Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation 2007;115:361-7.
Cronk LB, Ye B, Kaku T, et al. Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3. Heart Rhythm 2007;4:161-6.
Tester DJ, Dura M, Carturan E, et al. A mechanism for sudden infant death syndrome (SIDS): stress-induced leak via ryanodine receptors. Heart Rhythm 2007;4:733-9.
Van Norstrand DW, Valdivia CR, Tester DJ, et al. Molecular and functional characterization of novel glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) mutations in sudden infant death syndrome. Circulation 2007;116:2253-9.
Cheng J, Van Norstrand DW, Medeiros-Domingo A, et al. α-1 syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current. Circ Arrhythmia Electrophysiol 2009;2:667-76.
Ueda K, Valdivia CR, Medeiros-Domingo A, et al. Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex. Proc Natl Acad Sci U S A 2008;105:9355-60.
Wu G, Ai T, Kim JJ, et al. Alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption. Circ Arrhythmia Electrophysiol 2008;1:193-201.
Nagatomo T, Fan Z, Ye B, et al. Temperature dependence of early and late currents in human cardiac wild- type and long Q-T DeltaKPQ Na+ channels. Am J Physiol 1998;275:H2016-24.
Ackerman MJ, Siu BL, Sturner WQ, et al. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA 2001;286:2264-9.
Adams ME, Butler MH, Dwyer TM, et al. Two forms of mouse syntrophin, a 58 kd dystrophin-associated protein, differ in primary structure and tissue distribution. Neuron 1993;11:531-40.
Adams ME, Dwyer TM, Dowler LL, et al. Mouse alpha 1- and beta 2-syntrophin gene structure, chromosome localization, and homology with a discs large domain. J Biol Chem 1995;270:25859-65.
Gavillet B, Rougier JS, Domenighetti AA, et al. Cardiac sodium channel Nav1.5 is regulated by a multiprotein complex composed of syntrophins and dystrophin. Circ Res 2006;99:407-14.
Gee SH, Madhavan R, Levinson SR, et al. Interaction of muscle and brain sodium channels with multiple members of the syntrophin family of dystrophin-associated proteins. J Neurosci 1998;18:128-37.
Connors NC, Adams ME, Froehner SC, Kofuji P. The potassium channel Kir4.1 associates with the dystrophin-glycoprotein complex via alpha-syntrophin in glia. J Biol Chem 2004;279:28387-92.
Vandebrouck A, Sabourin J, Rivet J, et al. Regulation of capacitative calcium entries by alpha1-syntrophin: association of TRPC1 with dystrophin complex and the PDZ domain of alpha1-syntrophin. FASEB J 2007;21:608-17.
Sabourin J, Lamiche C, Vandebrouck A, et al. Regulation of TRPC1 and TRPC4 cation channels requires an alpha-syntrophin-dependent complex in skeletal mouse myotubes. J Biol Chem 2009;284:36248-61.
Lyssand JS, DeFino MC, Tang XB, et al. Blood pressure is regulated by an alpha1D-adrenergic receptor/dystrophin signalosome. J Biol Chem 2008;283:18792-800.
Marin MC, Jost CA, Brooks LA, et al. A common polymorphism acts as an intragenic modifier of mutant p53 behaviour. Nat Genet 2000;25:47-54.
Vikhanskaya F, Siddique MM, Kei Lee M, et al. Evaluation of the combined effect of p53 codon 72 polymorphism and hotspot mutations in response to anticancer drugs. Clin Cancer Res 2005;11:4348-56.
Whibley C, Pharoah PD, Hollstein M. p53 polymorphisms: cancer implications. Nat Rev Cancer 2009;9:95-107.
- Abstract views: 1238
- PDF: 1876
Copyright (c) 2011 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
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.