A mechanism for sudden infant death syndrome (SIDS): Stress-induced leak via ryanodine receptors

David J. Tester, Miroslav Dura, Elisa Carturan, Steven Reiken, Anetta Wronska, Andrew R. Marks, Michael John Ackerman

Research output: Contribution to journalArticle

122 Citations (Scopus)

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 [Ca 2+]), 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.

Original languageEnglish (US)
Pages (from-to)733-739
Number of pages7
JournalHeart Rhythm
Volume4
Issue number6
DOIs
StatePublished - Jun 2007

Fingerprint

Ryanodine Receptor Calcium Release Channel
Sudden Infant Death
Mutation
Diastole
HEK293 Cells
Sympathetic Nervous System
Infant Mortality
Lipid Bilayers
Missense Mutation
Amino Acid Substitution
Heat-Shock Proteins
Site-Directed Mutagenesis
Cyclic AMP-Dependent Protein Kinases
DNA Sequence Analysis
Hispanic Americans
Cardiac Arrhythmias
Alleles
High Pressure Liquid Chromatography
Phosphorylation
Phenotype

Keywords

  • Electrophysiology
  • Genetics
  • Ion channels
  • Pediatrics
  • Sudden death

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

A mechanism for sudden infant death syndrome (SIDS) : Stress-induced leak via ryanodine receptors. / Tester, David J.; Dura, Miroslav; Carturan, Elisa; Reiken, Steven; Wronska, Anetta; Marks, Andrew R.; Ackerman, Michael John.

In: Heart Rhythm, Vol. 4, No. 6, 06.2007, p. 733-739.

Research output: Contribution to journalArticle

Tester, David J. ; Dura, Miroslav ; Carturan, Elisa ; Reiken, Steven ; Wronska, Anetta ; Marks, Andrew R. ; Ackerman, Michael John. / A mechanism for sudden infant death syndrome (SIDS) : Stress-induced leak via ryanodine receptors. In: Heart Rhythm. 2007 ; Vol. 4, No. 6. pp. 733-739.
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T1 - A mechanism for sudden infant death syndrome (SIDS)

T2 - Stress-induced leak via ryanodine receptors

AU - Tester, David J.

AU - Dura, Miroslav

AU - Carturan, Elisa

AU - Reiken, Steven

AU - Wronska, Anetta

AU - Marks, Andrew R.

AU - Ackerman, Michael John

PY - 2007/6

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N2 - 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 [Ca 2+]), 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.

AB - 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 [Ca 2+]), 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.

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KW - Ion channels

KW - Pediatrics

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