Alpha1-syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current.

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. (2009). Alpha1-syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current. Circulation. Arrhythmia and electrophysiology, 2(6), pp. 667-676. Lippincott Williams & Wilkins 10.1161/CIRCEP.109.891440

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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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology
UniBE Contributor:	Medeiros Domingo, Argelia
Subjects:	600 Technology > 610 Medicine & health
ISSN:	1941-3084
Publisher:	Lippincott Williams & Wilkins
Language:	English
Submitter:	Argelia Medeiros Domingo
Date Deposited:	19 Jun 2014 11:24
Last Modified:	05 Dec 2022 14:28
Publisher DOI:	10.1161/CIRCEP.109.891440
PubMed ID:	20009079
URI:	https://boris.unibe.ch/id/eprint/42280