Alpha1-syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current.
In: Circulation: Arrhythmia & Electrophysiology, Jg. 2 (2009-12-01), Heft 6, S. 667-676
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Background: Sudden infant death syndrome (SIDS) is a leading cause of death during the first 6 months after birth. About 5% to 10% of SIDS may stem from cardiac channelopathies such as long-QT syndrome. We recently implicated mutations in alpha1-syntrophin (SNTA1) as a novel cause of long-QT syndrome, whereby mutant SNTA1 released inhibition of associated neuronal nitric oxide synthase by the plasma membrane Ca-ATPase PMCA4b, causing increased peak and late sodium current (I(Na)) via S-nitrosylation of the cardiac sodium channel. This study determined the prevalence and functional properties of SIDS-associated SNTA1 mutations. Methods and Results: Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing of SNTA1's open reading frame, 6 rare (absent in 800 reference alleles) missense mutations (G54R, P56S, T262P, S287R, T372M, and G460S) were identified in 8 (approximately 3%) of 292 SIDS cases. These mutations were engineered using polymerase chain reaction-based overlap extension and were coexpressed heterologously with SCN5A, neuronal nitric oxide synthase, and PMCA4b in HEK293 cells. I(Na) was recorded using the whole-cell method. A significant 1.4- to 1.5-fold increase in peak I(Na) and 2.3- to 2.7-fold increase in late I(Na) compared with controls was evident for S287R-, T372M-, and G460S-SNTA1 and was reversed by a neuronal nitric oxide synthase inhibitor. These 3 mutations also caused a significant depolarizing shift in channel inactivation, thereby increasing the overlap of the activation and inactivation curves to increase window current. Conclusions: Abnormal biophysical phenotypes implicate mutations in SNTA1 as a novel pathogenic mechanism for the subset of channelopathic SIDS. Functional studies are essential to distinguish pathogenic perturbations in channel interacting proteins such as alpha1-syntrophin from similarly rare but innocuous ones. [ABSTRACT FROM AUTHOR]
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Alpha1-syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current.
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Autor/in / Beteiligte Person: | Cheng, Jianding ; Van Norstrand, David W. ; Medeiros-Domingo, Argelia ; Valdivia, Carmen ; Tan, Bi-hua ; Ye, Bin ; Kroboth, Stacie ; Vatta, Matteo ; Tester, David J. ; January, Craig T. ; Makielski, Jonathan C. ; Ackerman, Michael J. |
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Zeitschrift: | Circulation: Arrhythmia & Electrophysiology, Jg. 2 (2009-12-01), Heft 6, S. 667-676 |
Veröffentlichung: | 2009 |
Medientyp: | academicJournal |
ISSN: | 1941-3149 (print) |
DOI: | 10.1161/CIRCEP.109.891440 |
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