In this model, we provide an integrated view of Sudden Infant Death Syndrome (SIDS) at the level of implicated tissues, signaling networks and genetics. The purpose of this model is to serve as an overview of research in this field and recommend new candidates for more focused or genome wide analyses. SIDS is the sudden and unexpected death of an infant (less than 1 year of age), almost always during deep sleep, where no cause of death can be found by autopsy. Factors that mediate SIDS are likely to be both biological and behavioral, such as sleeping position, environment and stress during a critical phase of infant development (http://www.nichd.nih.gov/health/topics/Sudden_Infant_Death_Syndrome.cfm). While no clear diagnostic markers currently exist, several polymorphisms have been identified which are significantly over-represented in distinct SIDS ethnic population. The large majority of these polymorphisms exist in genes associated with neuronal signaling, cardiac contraction and inflammatory response. These and other lines of evidence suggest that SIDS has a strong autonomic nervous system component (PMID:12350301). One of the neuronal nuclei most strongly implicated in SIDS has been the raphe nucleus of the brain stem. In this nuclei there are ultrastructural, cellular and molecular changes associated with SIDS relative to controls (PMID:19342987). This region of the brain is responsible for the large majority of serotonin that is produced in the human body and is functionally important in the regulation of normal cardiopulmonary activity, sleep and thermoregulation (see associated references).
Genes associated with serotonin synthesis and receptivity have some of the strongest genetic association with SIDS. Principle among these genes is the serotonin transporter SLC6A4 and the serotonin receptor HTR1A. SLC6A4 exhibits decreased expression in the raphe nucleus of the medulla oblongata and polymorphisms specifically associated with SIDS (PMID:19342987). In 75% of infants with SIDS, there is decreased HTR1A expression relative to controls along with an increase in the number of raphe serotonin neurons (PMID:19342987). Over-expression of the mouse orthologue of the HTR1A gene in the juvenile mouse medulla produces an analogous phenotype to SIDS with death due to bradycardia and hypothermia (PMID:18599790). These genes as well as those involved in serotonin synthesis are predicted to be transcriptionally regulated by a common factor, FEV (human orthologue of PET-1). PET-1 knock-out results in up to a 90% loss of serotonin neurons (PMID:12546819), while polymorphisms in FEV are over-represented in African American infants with SIDS. In addition to FEV, other transcription factors implicated in the regulation of these genes (Putative transcriptional regulators (TRs)) and FEV are also listed (see associated references). In addition to serotonin, vasopressin signaling and its regulation by serotonin appear to be important in a common pathway of cardiopulmonary regulation (PMID:2058745). A protein that associates with vasopressin signaling, named pituitary adenylate cyclase-activating polypeptide (ADCYAP1), results in a SIDS like phenotype, characterized by a high increase in spontaneous neonatal death, exacerbated by hypothermia and hypoxia (PMID:14608012), when disrupted in mice. Protein for this gene is widely distributed throughout the central nervous system (CNS), including autonomic control centers (PMID:12389210). ADCYAP1 and HTR1A are both predicted to be transcriptionally regulated by REST promoter binding. Regulation of G-protein coupled signaling pathways is illustrated for these genes, however, it is not clear whether ADCYAP1 acts directly upon raphe serotonin neurons.
Another potentially important class of receptors in SIDS is nicotine. Receptors for nicotine are expressed in serotonin neurons of the raphe throughout development (PMID:18986852). Application of nicotine or cigarette smoke is sufficient to inhibit electrical activity of raphe serotonin neurons (PMID:17515803) and chronic nicotine infusion in rats decreases expression of SLC6A4 (PMID:18778441). Furthermore, nicotine exposure reduces both HTR1A and HTR2A immunoreactivity in several nuclei of the brainstem (PMID:17451658).
In addition to CNS abnormalities, several studies have identified a critical link between cardiac arrhythmia (long QT syndrome) and SIDS (PMID:18928334). A number of genetic association studies identified functionally modifying mutations in critical cardiac channels in as many as 10% of all SIDS cases (PMID:18928334). These mutations have been predicted to predispose infants for long QT syndrome and sudden death. The highest proportion of SIDS associated mutations (both inherited and sporadic) is found in the sodium channel gene SCN5A. Examination of putative transcriptional regulators for these genes, highlights a diverse set of factors as well as a relatively common one (SP1).
Finally, several miscellaneous mutations have been identified in genes associated with inflammatory response and thermoregulation. Infection is considered a significant risk factor for SIDS (PMID:19114412). For inflammatory associated genes, such as TNF alpha, interleukin 10 and complement component 4, many of these mutations are only significant in the presence of infection and SIDS. In addition to these mutations, cerebrospinal fluid levels of IL6 are increased in SIDS cases as well as IL6R levels in the arcuate nucleus of the brain, another major site of serotonin synthesis (PMID:19396608). Genes such as ILR6 and ADCYAP1 are also associated with autoimmune disorders, thus SIDS may also be associated with autoinflammation of autonomic centers in the brain. Regulation of thermogenesis by brown adipose tissue has been proposed be an important component of SIDS, given that SIDS incidence is highest in the winter time and that animal models of SIDS demonstrate variation in body temperature. Interestingly, activation of raphe HTR1A decreases both shivering and peripheral vasoconstriction in piglets (18094064). Although a putative significant polymorphism was identified in the thermoregulator gene HSP60, this only occurred in one SIDS case. It is important to note that in the large majority of all these studies, sleeping position and smoking were among the most significant risk factors for SIDS.
In loving memory of Milo Salomonis (http://www.milosalomonis.org).This pathway was inferred from Homo sapiens pathway [http://www.wikipathways.org/index.php?title=Pathway:WP706&oldid=30282 WP706(r30282)] with a 93% conversion rate.b1ed43e42a9cca6acbbd6e4ce6ad78Contains an alternative promoter in the first and possibly second intron.aafa47cc5fb7deef67d78febd17d49bebf86e1dd49a89ceebebd49d49e31cc5d49eabeaba37aafaafaafaafa89bebab2ebaa9cceac3acd0e08c3ae08dbdcd0cd0c3acd0cd0e08c3ad43e08c3ac88c20a34e77fb7"Thus, Nkx2.2, Mash1, Gata-2, Lmx1b, and Phox2b may directly interact with the 1.8 kb region to control the proper spatiotemporal activation of Pet-1." PMID: 15758173; Pet1 together with Lmx1b, Nkx2.2, Mash1, Gata2, Gata3, and Phox2b form a transcriptional network, which specifies the differentiation of serotonergic neurons around embryonic day 11 in the mouse. PMID: 17142880fb7f67cc5serotonin signaling pathwayPW:0000854Pathway OntologySIDSDOID:9007Human Disease Ontology15199055PubMedRORalpha regulates the expression of genes involved in lipid homeostasis in skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of ROR.J Biol Chem2004Lau PNixon SJParton RGMuscat GE17360901PubMedDifferential regulation of the serotonin transporter gene by lithium is mediated by transcription factors, CCCTC binding protein and Y-box binding protein 1, through the polymorphic intron 2 variable number tandem repeat.J Neurosci2007Roberts JScott ACHoward MRBreen GBubb VJKlenova EQuinn JP16467535PubMedCell-specific repressor or enhancer activities of Deaf-1 at a serotonin 1A receptor gene polymorphism.J Neurosci2006Czesak MLemonde SPeterson EARogaeva AAlbert PR18639564PubMedTranscriptional regulation at a HTR1A polymorphism associated with mental illness.Neuropharmacology2008Le Francois BCzesak MSteubl DAlbert PR15758173PubMedA differentially autoregulated Pet-1 enhancer region is a critical target of the transcriptional cascade that governs serotonin neuron development.J Neurosci2005Scott MMKrueger KCDeneris ES9602135PubMedWinged helix hepatocyte nuclear factor 3 and POU-domain protein brn-2/N-oct-3 bind overlapping sites on the neuronal promoter of human aromatic L-amino acid decarboxylase gene.Brain Res Mol Brain Res1998Raynal JFDugast CLe Van Thai AWeber MJ14741405PubMedCooperative dimerization of the POU domain protein Brn-2 on a new motif activates the neuronal promoter of the human aromatic L-amino acid decarboxylase gene.Brain Res Mol Brain Res2004Dugast-Darzacq CEgloff SWeber MJ18286597PubMedGenetic variation in the HTR1A gene and sudden infant death syndrome.Am J Med Genet A2008Morley MERand CMBerry-Kravis EMZhou LFan WWeese-Mayer DE19120039PubMedSudden infant death syndrome (SIDS) in African Americans: polymorphisms in the gene encoding the stress peptide pituitary adenylate cyclase-activating polypeptide (PACAP).Acta Paediatr2009Cummings KJKlotz CLiu WQWeese-Mayer DEMarazita MLCooper MEBerry-Kravis EMTobias RGoldie CBech-Hansen NTWilson RJ18041756PubMedCongenital central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death.Pediatr Pulmonol2008Gronli JOSantucci BALeurgans SEBerry-Kravis EMWeese-Mayer DE16938762PubMedThe G protein beta3 subunit 825C allele is associated with sudden infant death due to infection.Acta Paediatr2006Hauge Opdal SMelien ORootwelt HVege AArnestad MOle Rognum T19278673PubMedPositron Emission Tomography Quantification of Serotonin-1A Receptor Binding in Medication-Free Bipolar Depression.Biol Psychiatry2009Sullivan GMOgden RTOquendo MAKumar JSSimpson NHuang YYMann JJParsey RV14608012PubMedSudden neonatal death in PACAP-deficient mice is associated with reduced respiratory chemoresponse and susceptibility to apnoea.J Physiol2004Cummings KJPendlebury JDSherwood NMWilson RJ19342987PubMedSudden Infant Death Syndrome and Sudden Intrauterine Unexplained Death: Correlation Between Hypoplasia of Raphe Nuclei and Serotonin Transporter Gene Promoter Polymorphism.Pediatr Res2009Lavezzi AMCasale VOneda RWeese-Mayer DEMatturri L17597646PubMedSudden infant death syndrome: rare mutation in the serotonin system FEV gene.Pediatr Res2007Rand CMBerry-Kravis EMZhou LFan WWeese-Mayer DE18771483PubMedHTR2A variation and sudden infant death syndrome: a case-control analysis.Acta Paediatr2009Rand CMBerry-Kravis EMFan WWeese-Mayer DE18675942PubMedPHOX2B mutations and ventilatory control.Respir Physiol Neurobiol2008Gallego JDauger S16275016PubMedIncreased serotonin receptor availability in human sleep: evidence from an [18F]MPPF PET study in narcolepsy.Neuroimage2006Derry CBenjamin CBladin Ple Bars DTochon-Danguy HBerkovic SFZimmer LCostes NMulligan RReutens D10094440PubMedThe complement component C4 in sudden infant death.Eur J Pediatr1999Opdal SHVege AStave AKRognum TO18928334PubMedCardiomyopathic and Channelopathic Causes of Sudden, Unexpected Death in Infants and Children.Annu Rev Med2008Tester DJAckerman M15240857PubMedSudden infant death syndrome: case-control frequency differences at genes pertinent to early autonomic nervous system embryologic development.Pediatr Res2004Weese-Mayer DEBerry-Kravis EMZhou LMaher BSCurran MESilvestri JMMarazita ML17077377PubMedMultiple serotonergic brainstem abnormalities in sudden infant death syndrome.JAMA2006Paterson DSTrachtenberg FLThompson EGBelliveau RABeggs AHDarnall RChadwick AEKrous HFKinney HC16830328PubMedSudden infant death syndrome: Case-control frequency differences in paired like homeobox (PHOX) 2B gene.Am J Med Genet A2006Rand CMWeese-Mayer DEZhou LMaher BSCooper MEMarazita MLBerry-Kravis EM18810510PubMedAssociation of dopamine transporter and monoamine oxidase molecular polymorphisms with sudden infant death syndrome and stillbirth: new insights into the serotonin hypothesis.Neurogenetics2009Filonzi LMagnani CLavezzi AMRindi GParmigiani SBevilacqua GMatturri LNonnis Marzano F18633768PubMedTNF-alpha and IL-10 gene polymorphisms versus cardioimmunological responses in sudden infant death.Fetal Pediatr Pathol2008Perskvist NSkoglund KEdston EBackstrom GLodestad IPalm U18192214PubMedGenomic structure, transcriptional control, and tissue distribution of HERG1 and KCNQ1 genes.Am J Physiol Heart Circ Physiol2008Luo XXiao JLin HLu YYang BWang Z8841406PubMedCloning and characterization of the 5'-upstream regulatory region of the Ca(2+)-release channel gene of cardiac sarcoplasmic reticulum.Eur J Biochem1996Nishida KOtsu KHori MKuzuya TTada M17613521PubMedRegulation of tryptophan hydroxylase-2 gene expression by a bipartite RE-1 silencer of transcription/neuron restrictive silencing factor (REST/NRSF) binding motif.J Biol Chem2007Patel PDBochar DATurner DLMeng FMueller HMPontrello CG14756806PubMedCell type-dependent recruitment of trichostatin A-sensitive repression of the human 5-HT1A receptor gene.J Neurochem2004Lemonde SRogaeva AAlbert PR17556193PubMedA mechanism for sudden infant death syndrome (SIDS): stress-induced leak via ryanodine receptors.Heart Rhythm2007Tester DJDura MCarturan EReiken SWronska AMarks ARAckerman MJ18571009PubMedTNF-alpha promoter polymorphisms in sudden infant death.Hum Immunol2008Ferrante LOpdal SHVege ARognum TO15056938PubMed[The regulatory mechanism for neuron specific expression of PACAP gene]Nippon Yakurigaku Zasshi2004Miyata ASugawara HIwata SShimizu TKangawa K19396608PubMedInterleukin-6 and the serotonergic system of the medulla oblongata in the sudden infant death syndrome.Acta Neuropathol2009Rognum IJHaynes RLVege AYang MRognum TOKinney HC16728402PubMedGlucocorticoid and androgen activation of monoamine oxidase A is regulated differently by R1 and Sp1.J Biol Chem2006Ou XMChen KShih JC8957963PubMedHuman heat shock protein gene polymorphisms and sudden infant death syndrome.Arch Dis Child1996Rahim RABoyd PAAinslie Patrick WJBurdon RH17568567PubMedCharacterization of a functional promoter polymorphism of the human tryptophan hydroxylase 2 gene in serotonergic raphe neurons.Biol Psychiatry2007Scheuch KLautenschlager MGrohmann MStahlberg SKirchheiner JZill PHeinz AWalther DJPriller J16006741PubMedTranscriptional regulation of neuronal genes and its effect on neural functions: cumulative mRNA expression of PACAP and BDNF genes controlled by calcium and cAMP signals in neurons.J Pharmacol Sci2005Fukuchi MTabuchi ATsuda M18032528PubMedNF-kappaB-dependent transcriptional regulation of the cardiac scn5a sodium channel by angiotensin II.Am J Physiol Cell Physiol2008Shang LLSanyal SPfahnl AEJiao ZAllen JLiu HDudley SC Jr10575032PubMedThe ETS domain factor Pet-1 is an early and precise marker of central serotonin neurons and interacts with a conserved element in serotonergic genes.J Neurosci1999Hendricks TFrancis NFyodorov DDeneris ES17311278PubMedOverexpression HERG K(+) channel gene mediates cell-growth signals on activation of oncoproteins SP1 and NF-kappaB and inactivation of tumor suppressor Nkx3.1.J Cell Physiol2007Lin HXiao JLuo XWang HGao HYang BWang Z12065627PubMedInvolvement of NF-Y and Sp1 in basal and cAMP-stimulated transcriptional activation of the tryptophan hydroxylase (TPH ) gene in the pineal gland.J Neurochem2002Cote FSchussler NBoularand SPeirotes AThevenot EMallet JVodjdani G9645961PubMedCBF/NF-Y activates transcription of the human tryptophan hydroxylase gene through an inverted CCAAT box.Brain Res Mol Brain Res1998Teerawatanasuk NCarr LG2058745PubMedVasopressin and autonomic mechanisms mediate cardiovascular actions of central serotonin.Am J Physiol1991Pergola PEAlper RH19369586PubMedSevere spontaneous bradycardia associated with respiratory disruptions in rat pups with fewer brainstem 5-HT neurons.Am J Physiol Regul Integr Comp Physiol2009Cummings KJCommons KGFan KCLi ANattie EE17142880PubMedSpecification and differentiation of serotonergic neurons.Stem Cell Rev2006Alenina NBashammakh SBader M18094064PubMedActivation of 5-HT1A receptors in medullary raphe disrupts sleep and decreases shivering during cooling in the conscious piglet.Am J Physiol Regul Integr Comp Physiol2008Brown JWSirlin EABenoit AMHoffman JMDarnall RA17869437PubMed5-HT(2) receptor subtypes mediate different long-term changes in GABAergic activity to parasympathetic cardiac vagal neurons in the nucleus ambiguus.Neuroscience2007Dergacheva OGriffioen KJWang XKamendi HGorini CMendelowitz D18778441PubMedChronic effect of nicotine on serotonin transporter mRNA in the raphe nucleus of rats: reversal by co-administration of bupropion.Psychiatry Clin Neurosci2008Semba JWakuta M16144830PubMedPHOX2B regulates its own expression by a transcriptional auto-regulatory mechanism.J Biol Chem2005Cargnin FFlora ADi Lascio SBattaglioli ELonghi RClementi FFornasari D