title: Alpha1-syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current.
abstract: 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.
  
  
  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.
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI, USA.
authors.forename: Jianding
authors.initials: J
authors.lastname: Cheng
authors.forename: David W
authors.initials: DW
authors.lastname: Van Norstrand
authors.forename: Argelia
authors.initials: A
authors.lastname: Medeiros-Domingo
authors.forename: Carmen
authors.initials: C
authors.lastname: Valdivia
authors.forename: Bi-hua
authors.initials: BH
authors.lastname: Tan
authors.forename: Bin
authors.initials: B
authors.lastname: Ye
authors.forename: Stacie
authors.initials: S
authors.lastname: Kroboth
authors.forename: Matteo
authors.initials: M
authors.lastname: Vatta
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Craig T
authors.initials: CT
authors.lastname: January
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004252:DNA Mutational Analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015640:Ion Channel Gating; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009124:Muscle Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D016366:Open Reading Frames; D018408:Patch-Clamp Techniques; D010641:Phenotype; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism; D051381:Rats; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013398:Sudden Infant Death / Q000235:genetics*; D013997:Time Factors; D014162:Transfection
chemical_list: D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; C568322:Scn5a protein, rat; D015222:Sodium Channels; C091825:syntrophin alpha1; D012964:Sodium; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D053499:Plasma Membrane Calcium-Transporting ATPases