TY - JOUR
T1 - α1-Syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current
AU - Ackerman, Michael J.
AU - Cheng, Jianding
AU - Van Norstrand, David W.
AU - Medeiros-Domingo, Argelia
AU - Valdivia, Carmen
AU - Tan, Bi Hua
AU - Ye, Bin
AU - Kroboth, Stacie
AU - Vatta, Matteo
AU - Tester, David J.
AU - January, Craig T.
AU - Makielski, Jonathan C.
PY - 2009/12
Y1 - 2009/12
N2 - 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 α1-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 (INa) 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 (≈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 INa and 2.3- to 2.7-fold increase in late INa 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 α1-syntrophin from similarly rare but innocuous ones. (Circ Arrhythm Electrophysiol. 2009;2:667-676.)
AB - 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 α1-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 (INa) 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 (≈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 INa and 2.3- to 2.7-fold increase in late INa 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 α1-syntrophin from similarly rare but innocuous ones. (Circ Arrhythm Electrophysiol. 2009;2:667-676.)
UR - http://www.scopus.com/inward/record.url?scp=73949159312&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=73949159312&partnerID=8YFLogxK
U2 - 10.1161/CIRCEP.109.891440
DO - 10.1161/CIRCEP.109.891440
M3 - Article
C2 - 20009079
AN - SCOPUS:73949159312
SN - 1941-3149
VL - 2
SP - 667
EP - 676
JO - Circulation: Arrhythmia and Electrophysiology
JF - Circulation: Arrhythmia and Electrophysiology
IS - 6
ER -