title: A mechanism for sudden infant death syndrome (SIDS): stress-induced leak via ryanodine receptors.
abstract: BACKGROUND
  Sudden infant death syndrome (SIDS) is the leading cause of postneonatal mortality in the United States. Mutations in the RyR2-encoded cardiac ryanodine receptor cause the highly lethal catecholaminergic polymorphic ventricular tachycardia (CPVT1) in the young.
  
  
  OBJECTIVE
  The purpose of this study was to determine the spectrum and prevalence of RyR2 mutations in a large cohort of SIDS cases.
  
  
  METHODS
  Using polymerase chain reaction, denaturing high performance liquid chromatography, and direct DNA sequencing, a targeted mutational analysis of RyR2 was performed on genomic DNA isolated from frozen necropsy tissue on 134 unrelated cases of SIDS (57 females, 77 males; 83 white, 50 black, 1 Hispanic; average age = 2.7 months). RyR2 mutations were engineered by site-directed mutagenesis, heterologously expressed in HEK293 cells, and functionally characterized using single-channel recordings in planar lipid bilayers.
  
  
  RESULTS
  Overall, two distinct and novel RyR2 mutations were identified in two cases of SIDS. A 6-month-old black female hosted an R2267H missense mutation, and a 4-week-old white female infant harbored a S4565R mutation. Both nonconservative amino acid substitutions were absent in 400 reference alleles, involved conserved residues, and were localized to key functionally significant domains. Under conditions that simulate stress [Protein Kinase A (PKA) phosphorylation] during diastole (low activating [Ca2+]), SIDS-associated RyR2 mutant channels displayed a significant gain-of-function phenotype consistent with the functional effect of previously characterized CPVT-associated RyR2 mutations.
  
  
  CONCLUSIONS
  Here we report a novel pathogenic mechanism for SIDS, whereby SIDS-linked RyR2 mutations alter the response of the channels to sympathetic nervous system stimulation such that during stress the channels become "leaky" and thus potentially trigger fatal cardiac arrhythmias.
authors.affiliation: Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota 55901, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Miroslav
authors.initials: M
authors.lastname: Dura
authors.forename: Elisa
authors.initials: E
authors.lastname: Carturan
authors.forename: Steven
authors.initials: S
authors.lastname: Reiken
authors.forename: Anetta
authors.initials: A
authors.lastname: Wronska
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D000222:Adaptation, Physiological; D002395:Catecholamines; D004594:Electrophysiology; D005260:Female; D006801:Humans; D007223:Infant; D007473:Ion Channels; D008297:Male; D009154:Mutation; D010865:Pilot Projects; D016133:Polymerase Chain Reaction; D015995:Prevalence; D012307:Risk Factors; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D013312:Stress, Physiological / Q000150:complications / Q000473:pathology*; D013398:Sudden Infant Death / Q000235:genetics* / Q000473:pathology; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000473:pathology
chemical_list: D002395:Catecholamines; D007473:Ion Channels; D019837:Ryanodine Receptor Calcium Release Channel