alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption.
BACKGROUND
Long-QT syndrome (LQTS) is an inherited disorder associated with sudden cardiac death. The cytoskeletal protein syntrophin-alpha(1) (SNTA1) is known to interact with the cardiac sodium channel (hNa(v)1.5), and we hypothesized that SNTA1 mutations might cause phenotypic LQTS in patients with genotypically normal hNa(v)1.5 by secondarily disturbing sodium channel function.


RESULTS
Mutational analysis of SNTA1 was performed on 39 LQTS patients (QTc> or =480 ms) with previously negative genetic screening for the known LQTS-causing genes. We identified a novel A257G-SNTA1 missense mutation, which affects a highly conserved residue, in 3 unrelated LQTS probands but not in 400 ethnic-matched control alleles. Only 1 of these probands had a preexisting family history of LQTS and sudden death with an additional intronic variant in KCNQ1. Electrophysiological analysis was performed using HEK-293 cells stably expressing hNa(v)1.5 and transiently transfected with either wild-type or mutant SNTA1 and, in neonatal rat cardiomyocytes, transiently transfected with either wild-type or mutant SNTA1. In both HEK-293 cells and neonatal rat cardiomyocytes, increased peak sodium currents were noted along with a 10-mV negative shift of the onset and peak of currents of the current-voltage relationships. In addition, A257G-SNTA1 shifted the steady-state activation (V(h)) leftward by 9.4 mV, whereas the voltage-dependent inactivation kinetics and the late sodium currents were similar to wild-type SNTA1.


CONCLUSIONS
SNTA1 is a new susceptibility gene for LQTS. A257G-SNTA1 can cause gain-of-function of Na(v)1.5 similar to the LQT3.
Wu
Geru
G
Electrophysiology Research Laboratory, Texas Heart Institute/St. Luke's Episcopal Hospital, Houston, Texas, USA.
Ai
Tomohiko
T
Kim
Jeffrey J
JJ
Mohapatra
Bhagyalaxmi
B
Xi
Yutao
Y
Li
Zhaohui
Z
Abbasi
Shahrzad
S
Purevjav
Enkhsaikhan
E
Samani
Kaveh
K
Ackerman
Michael J
MJ
Qi
Ming
M
Moss
Arthur J
AJ
Shimizu
Wataru
W
Towbin
Jeffrey A
JA
Cheng
Jie
J
Vatta
Matteo
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000831:Animals, Newborn; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007223:Infant; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018408:Patch-Clamp Techniques; D051381:Rats; D015222:Sodium Channels / Q000378:metabolism*; D055815:Young Adult
D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D015222:Sodium Channels; C091825:syntrophin alpha1; D004247:DNA
J Biol Chem. 2003 Jan 17;278(3):1915-23
12429735
Heart Rhythm. 2007 Feb;4(2):161-6
17275750
Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20990-5
18093912
J Biol Chem. 2000 May 26;275(21):15851-60
10747910
J Cardiovasc Electrophysiol. 2000 May;11(5):601-2
10826942
Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13200-5
8917568
Circulation. 1995 Nov 15;92(10):2929-34
7586261
Nature. 2003 Feb 6;421(6923):634-9
12571597
Hum Mutat. 2003 May;21(5):552
12673799
Circulation. 2007 Jul 3;116(1):10-6
17576865
Circ Res. 2006 Aug 18;99(4):407-14
16857961
Clin Chim Acta. 2005 Nov;361(1-2):54-79
16002060
Neuron. 1993 Sep;11(3):531-40
7691103
J Biol Chem. 1995 Oct 27;270(43):25859-65
7592771
Circulation. 2005 Oct 18;112(16):2517-29
16230503
J Cardiovasc Electrophysiol. 2007 Apr;18(4):434-40
17331104
Circulation. 1993 Aug;88(2):782-4
8339437
J Neurosci. 1998 Jan 1;18(1):128-37
9412493
Circulation. 2006 Nov 14;114(20):2104-12
17060380
J Comput Biol. 1997 Fall;4(3):311-23
9278062
J Mol Cell Cardiol. 2008 Apr;44(4):633-46
18336833
Proc Natl Acad Sci U S A. 1994 May 10;91(10):4446-50
8183929
J Biol Chem. 1994 Feb 25;269(8):6040-4
8119949
Nat Clin Pract Cardiovasc Med. 2005 Jul;2(7):346-51
16265560