title: alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption.
abstract: 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.
authors.affiliation: Electrophysiology Research Laboratory, Texas Heart Institute/St. Luke's Episcopal Hospital, Houston, Texas, USA.
authors.forename: Geru
authors.initials: G
authors.lastname: Wu
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ai
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Kim
authors.forename: Bhagyalaxmi
authors.initials: B
authors.lastname: Mohapatra
authors.forename: Yutao
authors.initials: Y
authors.lastname: Xi
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Li
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Abbasi
authors.forename: Enkhsaikhan
authors.initials: E
authors.lastname: Purevjav
authors.forename: Kaveh
authors.initials: K
authors.lastname: Samani
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Ming
authors.initials: M
authors.lastname: Qi
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Moss
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
authors.forename: Matteo
authors.initials: M
authors.lastname: Vatta
mesh_terms: 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
chemical_list: D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D015222:Sodium Channels; C091825:syntrophin alpha1; D004247:DNA
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