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, PMID: 20124538). 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, PMID: 20124538). This region of the brain is responsible for the large majority of neuronal serotonin produced 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 the serotonin biosynthetic enzyme TPH2, 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).
Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP706 CPTAC Assay Portal].
b1ed43e42a9cca6acbb82d03bd6e4ce6ae18a8bb2fdcebc9b3bacff82b0bc0dd78Contains an alternative promoter in the first and possibly second intron.aafa47cc5fb7deef67d78febd17d49aaae94PMID: 9861170 PMID: 1317796KAP0 HUMANda4c21e96d3ae89a93a93d0ea35f1fb97b3dd73d5cfdbf8faebccebebf86e1dd49a89ceedb2bebd49d49cc5d49eabeaba37aafaafaafaafbebab2a9cff6cb1fb1d16cb1ff6bbbd6bf86d49cbbc71ed0d99f27cf2d2cba9fb5ceac3acd0e08a7ee08a7ec3ac3ae08eb1c3ac3adbdcd0cd0c3ac3acd0cd0c3ac3ad43b40a73e08a73e08c3abe9be9e08fc3a58a3ea52f6ccebd82f3bba9ba9ba9ed0c71eb1fb5e08cebcf2f27a3efc3f72c88c20a4ee6efc5bf5fdba34e77fb7f84"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: 17142880fb7d39dfaf67cc5c50f4de53ce4dd619369586PubMedSevere 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 EE19772970PubMedImpact of Sodium/Proton Exchanger 3 Gene Variants on Sudden Infant Death Syndrome.J Pediatr200919772970PubMedImpact of Sodium/Proton Exchanger 3 Gene Variants on Sudden Infant Death Syndrome.J Pediatr2009Poetsch MNottebaum BJWingenfeld LFrede SVennemann MBajanowski T9676432PubMedIsolation and functional analysis of alternative promoters in the human aquaporin-4 water channel gene.Genomics1998Umenishi FVerkman AS16275016PubMedIncreased 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 D11335745PubMedSerotonin transporter gene variation is a risk factor for sudden infant death syndrome in the Japanese population.Pediatrics2001Narita NNarita MTakashima SNakayama MNagai TOkado N17101276PubMedEvidence of HIF-1 functional binding activity to caspase-3 promoter after photothrombotic cerebral ischemia.Mol Cell Neurosci2007Van Hoecke MPrigent-Tessier ASGarnier PEBertrand NMFilomenko RBettaieb AMarie CBeley AG20965158PubMedActivation of tyrosine hydroxylase (TH) gene transcription induced by brain-derived neurotrophic factor (BDNF) and its selective inhibition through Ca(2+) signals evoked via the N-methyl-D-aspartate (NMDA) receptor.Brain Res2010Fukuchi MFujii HTakachi HIchinose HKuwana YTabuchi ATsuda M8957963PubMedHuman heat shock protein gene polymorphisms and sudden infant death syndrome.Arch Dis Child1996Rahim RABoyd PAAinslie Patrick WJBurdon RH19278673PubMedPositron Emission Tomography Quantification of Serotonin-1A Receptor Binding in Medication-Free Bipolar Depression.Biol Psychiatry2009Sullivan GMOgden RTOquendo MAKumar JSSimpson NHuang YYMann JJParsey RV18085326PubMedNHE3 in the human brainstem: implication for the pathogenesis of the sudden infant death syndrome (SIDS)?Adv Exp Med Biol2008Wiemann MFrede STschentscher FKKiwull-Schöne HKiwull PBingmann DBrinkmann BBajanowski T14575242PubMedNMDA receptor 1 expression in the brainstem of human infants and its relevance to the sudden infant death syndrome (SIDS).J Neuropathol Exp Neurol2003Machaalani RWaters KA16006741PubMedTranscriptional 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 M18639564PubMedTranscriptional regulation at a HTR1A polymorphism associated with mental illness.Neuropharmacology2008Le François BCzesak MSteubl DAlbert PR10978336PubMedTranscriptional repression of neurotrophin receptor trkB by thyroid hormone in the developing rat brain.J Biol Chem2000Pombo PMBarettino DEspliguero GMetsis MIglesias TRodriguez-Pena A17374610PubMedHypoxia-inducible factor-1 (HIF-1) is a transcriptional activator of the TrkB neurotrophin receptor gene.J Biol Chem2007Martens LKKirschner KMWarnecke CScholz H16916659PubMedAssociation of sudden infant death syndrome with VEGF and IL-6 gene polymorphisms.Hum Immunol2006Dashash MPravica VHutchinson IVBarson AJDrucker DB18928334PubMedCardiomyopathic and Channelopathic Causes of Sudden, Unexpected Death in Infants and Children.Annu Rev Med2008Tester DJAckerman M20080142PubMedIL-1 gene cluster polymorphisms and sudden infant death syndrome.Hum Immunol2010Ferrante LOpdal SHVege ARognum TO18599790PubMed22226696PubMedHistone deacetylase 9 as a negative regulator for choline acetyltransferase gene in NG108-15 neuronal cells.Neuroscience2012Aizawa STeramoto KYamamuro Y20198379PubMedA common FMO3 polymorphism may amplify the effect of nicotine exposure in sudden infant death syndrome (SIDS).Int J Legal Med2010Poetsch MCzerwinski MWingenfeld LVennemann MBajanowski T16764822PubMedRegulation of human tyrosine hydroxylase gene by neuron-restrictive silencer factor.Biochem Biophys Res Commun2006Kim SMYang JWPark MJLee JKKim SULee YSLee MAdisease pathwayPW:0000013Pathway Ontology17584746PubMedThe transcription factor Runx3 represses the neurotrophin receptor TrkB during lineage commitment of dorsal root ganglion neurons.J Biol Chem2007Inoue KIto KOsato MLee BBae SCIto Y12599191PubMedSudden infant death syndrome: association with a promoter polymorphism of the serotonin transporter gene.Am J Med Genet A2003Weese-Mayer DEBerry-Kravis EMMaher BSSilvestri JMCurran MEMarazita ML18571009PubMedTNF-alpha promoter polymorphisms in sudden infant death.Hum Immunol2008Ferrante LOpdal SHVege ARognum TO14741405PubMedCooperative 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 MJ7592771PubMedMouse alpha 1- and beta 2-syntrophin gene structure, chromosome localization, and homology with a discs large domain.J Biol Chem1995Adams MEDwyer TMDowler LLWhite RAFroehner SC18675942PubMedPHOX2B mutations and ventilatory control.Respir Physiol Neurobiol2008Gallego JDauger S19801649PubMedMixed lineage kinase phosphorylates transcription factor E47 and inhibits TrkB expression to link neuronal death and survival pathways.J Biol Chem2009Pedraza NRafel MNavarro IEncinas MAldea MGallego C7745608PubMedPositive and negative effects of nuclear receptors on transcription activation by AP-1 of the human choline acetyltransferase proximal promoter.J Neurosci Res1995Schmitt MBausero PSimoni PQueuche DGeoffroy VMarschal CKempf JQuirin-Stricker C18286597PubMedGenetic variation in the HTR1A gene and sudden infant death syndrome.Am J Med Genet A2008Morley MERand CMBerry-Kravis EMZhou LFan WWeese-Mayer DE19958302PubMedCytokine gene polymorphisms and sudden infant death syndrome.Acta Paediatr2010Ferrante LOpdal SHVege ARognum T18032528PubMedNF-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 Jr14608012PubMedSudden neonatal death in PACAP-deficient mice is associated with reduced respiratory chemoresponse and susceptibility to apnoea.J Physiol2004Cummings KJPendlebury JDSherwood NMWilson RJ19841066PubMedProstaglandin promotion of osteocyte gap junction function through transcriptional regulation of connexin 43 by glycogen synthase kinase 3/beta-catenin signaling.Mol Cell Biol2010Xia XBatra NShi QBonewald LFSprague EJiang JX10575032PubMedThe 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 ES22418790PubMedProtein Kinase A-Dependent Substance P Expression by Pituitary Adenylate Cyclase-Activating Polypeptide in Rat Sensory Neuronal Cell Line ND7/23 Cells.J Mol Neurosci2012Inoue AOhnishi MFukutomi CKanoh MMiyauchi MTakata TTsuchiya DNishio H15273283PubMedMapping of sudden infant death with dysgenesis of the testes syndrome (SIDDT) by a SNP genome scan and identification of TSPYL loss of function.Proc Natl Acad Sci U S A2004Puffenberger EGHu-Lince DParod JMCraig DWDobrin SEConway ARDonarum EAStrauss KADunckley TCardenas JFMelmed KRWright CALiang WStafford PFlynn CRMorton DHStephan DA19559077PubMedEstrogen receptor beta regulates the expression of tryptophan-hydroxylase 2 mRNA within serotonergic neurons of the rat dorsal raphe nuclei.Neuroscience2009Donner NHanda RJ20847275PubMedmiR-16 targets the serotonin transporter: a new facet for adaptive responses to antidepressants.Science2010Baudry AMouillet-Richard SSchneider BLaunay JMKellermann O20937660PubMedEvidence for an association between infant mortality and a carnitine palmitoyltransferase 1A genetic variant.Pediatrics2010Gessner BDGillingham MBBirch SWood TKoeller DMserotonin signaling pathwayPW:0000854Pathway Ontologycardiac myocyteCL:0000746Cell Type16916793PubMedTranscriptional regulation of human MAP2 gene in melanoma: role of neuronal bHLH factors and Notch1 signaling.Nucleic Acids Res2006Bhat KMMaddodi NShashikant CSetaluri V8841406PubMedCloning 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 M11080175PubMedNuclear factor kappaB/p49 is a negative regulatory factor in nerve growth factor-induced choline acetyltransferase promoter activity in PC12 cells.J Neurochem2000Toliver-Kinsky TWood TPerez-Polo JR17142880PubMedSpecification and differentiation of serotonergic neurons.Stem Cell Rev200617142880PubMedSpecification and differentiation of serotonergic neurons.Stem Cell Rev2006Alenina NBashammakh SBader M17553693PubMedCa2+, CREB and krüppel: a novel KLF7-binding element conserved in mouse and human TRKB promoters is required for CREB-dependent transcription.Mol Cell Neurosci2007Kingsbury TJKrueger BK19120039PubMedSudden 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 RJ18778441PubMedChronic effect of nicotine on serotonin transporter mRNA in the raphe nucleus of rats: reversal by co-administration of bupropion.Psychiatry Clin Neurosci2008Semba JWakuta M18792810PubMedAssociation between the G1001C polymorphism in the GRIN1 gene promoter and schizophrenia in the Iranian population.J Mol Neurosci2009Galehdari HPooryasin AForoughmand ADaneshmand SSaadat M12393272PubMedSynergistic activation of the human choline acetyltransferase gene by c-Myb and C/EBPbeta.Brain Res Mol Brain Res2002Robert ISutter AQuirin-Stricker C9645961PubMedCBF/NF-Y activates transcription of the human tryptophan hydroxylase gene through an inverted CCAAT box.Brain Res Mol Brain Res1998Teerawatanasuk NCarr LG15240857PubMedSudden 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 ML17613521PubMedRegulation 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 CG18192214PubMedGenomic structure, transcriptional control, and tissue distribution of HERG1 and KCNQ1 genes.Am J Physiol Heart Circ Physiol2008Luo XXiao JLin HLu YYang BWang Z21555452PubMedA hypoxia-induced positive feedback loop promotes hypoxia-inducible factor 1alpha stability through miR-210 suppression of glycerol-3-phosphate dehydrogenase 1-like.Mol Cell Biol2011Kelly TJSouza ALClish CBPuigserver P9933599PubMedFunctional and cooperative interactions between the homeodomain PDX1, Pbx, and Prep1 factors on the somatostatin promoter.J Biol Chem1999Goudet GDelhalle SBiemar FMartial JAPeers B18384375PubMedSp1-like sequences mediate human caspase-3 promoter activation by p73 and cisplatin.FEBS J2008Sudhakar CJain NSwarup G20226894PubMedSudden infant death syndrome-associated mutations in the sodium channel beta subunits.Heart Rhythm2010Tan BHPundi KNVan Norstrand DWValdivia CRTester DJMedeiros-Domingo AMakielski JCAckerman MJ14756806PubMedCell type-dependent recruitment of trichostatin A-sensitive repression of the human 5-HT1A receptor gene.J Neurochem2004Lemonde SRogaeva AAlbert PR12065627PubMedInvolvement of NF-Y and Sp1 in basal and cAMP-stimulated transcriptional activation of the tryptophan hydroxylase (TPH ) gene in the pineal gland.J Neurochem2002Côté FSchussler NBoularand SPeirotes AThévenot EMallet JVodjdani G7908738PubMedThe Oct-2 transcription factor represses tyrosine hydroxylase expression via a heptamer TAATGARAT-like motif in the gene promoter.Nucleic Acids Res1994Dawson SJYoon SOChikaraishi DMLillycrop KALatchman DS20009079PubMedAlpha1-syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current.Circ Arrhythm Electrophysiol2009Cheng JVan Norstrand DWMedeiros-Domingo AValdivia CTan BHYe BKroboth SVatta MTester DJJanuary CTMakielski JCAckerman MJ19880519PubMedOncogenic BRAFV600E induces expression of neuronal differentiation marker MAP2 in melanoma cells by promoter demethylation and down-regulation of transcription repressor HES1.J Biol Chem2010Maddodi NBhat KMDevi SZhang SCSetaluri V16467535PubMedCell-specific repressor or enhancer activities of Deaf-1 at a serotonin 1A receptor gene polymorphism.J Neurosci2006Czesak MLemonde SPeterson EARogaeva AAlbert PR17597646PubMedSudden infant death syndrome: rare mutation in the serotonin system FEV gene.Pediatr Res2007Rand CMBerry-Kravis EMZhou LFan WWeese-Mayer DE20209124PubMedCardiac muscarinic receptor overexpression in sudden infant death syndrome.PLoS One2010Livolsi ANiederhoffer NDali-Youcef NRambaud COlexa CMokni WGies JPBousquet P18534229PubMedA functional polymorphism in the tyrosine hydroxylase gene indicates a role of noradrenalinergic signaling in sudden infant death syndrome.J Pediatr2008Klintschar MReichenpfader BSaternus KS17556193PubMedA mechanism for sudden infant death syndrome (SIDS): stress-induced leak via ryanodine receptors.Heart Rhythm2007Tester DJDura MCarturan EReiken SWronska AMarks ARAckerman MJ20880945PubMedVariant interleukin 1 receptor antagonist gene alleles in sudden infant death syndrome.Arch Dis Child2010Highet ARGibson CSGoldwater PN18810510PubMedAssociation 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 F2058745PubMedVasopressin and autonomic mechanisms mediate cardiovascular actions of central serotonin.Am J Physiol1991Pérgola PEAlper RH10094440PubMedThe complement component C4 in sudden infant death.Eur J Pediatr1999Opdal SHVege AStave AKRognum TO9602135PubMedWinged 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 Thaï AWeber MJ18771483PubMedHTR2A variation and sudden infant death syndrome: a case-control analysis.Acta Paediatr2009Rand CMBerry-Kravis EMFan 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 RJ22000980PubMedEffects of cigarette smoke exposure on nicotinic acetylcholine receptor subunits α7 and β2 in the sudden infant death syndrome (SIDS) brainstem.Toxicol Appl Pharmacol2011Machaalani RSay MWaters KA17311278PubMedOverexpression 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 Z19729586PubMedPrenatal nicotine-exposure alters fetal autonomic activity and medullary neurotransmitter receptors: implications for sudden infant death syndrome.J Appl Physiol2009Duncan JRGarland MMyers MMFifer WPYang MKinney HCStark RI17568567PubMedCharacterization 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 J22179534PubMedConnexin43 mutation causes heterogeneous gap junction loss and sudden infant death.Circulation2012Van Norstrand DWAsimaki ARubinos CDolmatova ESrinivas MTester DJSaffitz JEDuffy HSAckerman MJ22371606PubMedRepressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death.Proc Natl Acad Sci U S A2012Noh KMHwang JYFollenzi AAthanasiadou RMiyawaki TGreally JMBennett MVZukin RS17360901PubMedDifferential 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 JP21600882PubMedTranscriptional regulation of the Na⁺/H⁺ exchanger NHE3 by chronic exposure to angiotensin II in renal epithelial cells.Biochem Biophys Res Commun2011Queiroz-Leite GDPeruzzetto MCNeri EARebouças NA16144830PubMedPHOX2B regulates its own expression by a transcriptional auto-regulatory mechanism.J Biol Chem200516144830PubMedPHOX2B regulates its own expression by a transcriptional auto-regulatory mechanism.J Biol Chem2005Cargnin FFlora ADi Lascio SBattaglioli ELonghi RClementi FFornasari D16846370PubMedComparisons between transcriptional regulation and RNA expression in human embryonic stem cell lines.Stem Cells Dev2006Player AWang YBhattacharya BRao MPuri RKKawasaki ES15199055PubMedRORalpha 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 GE21865888PubMedDecreased GABAA receptor binding in the medullary serotonergic system in the sudden infant death syndrome.J Neuropathol Exp Neurol2011Broadbelt KGPaterson DSBelliveau RATrachtenberg FLHaas EAStanley CKrous HFKinney HC16938762PubMedThe G protein beta3 subunit 825C allele is associated with sudden infant death due to infection.Acta Paediatr2006Hauge Opdal SMelien ØRootwelt HVege AArnestad MOle Rognum T20351659PubMedAquaporin-4 gene variation and sudden infant death syndrome.Pediatr Res2010Opdal SHVege AStray-Pedersen ARognum TO18180303PubMedSurface expression of GABAA receptors is transcriptionally controlled by the interplay of cAMP-response element-binding protein and its binding partner inducible cAMP early repressor.J Biol Chem2008Hu YLund IVGravielle MCFarb DHBrooks-Kayal ARRussek SJSIDSDOID:9007Disease18633768PubMedTNF-alpha and IL-10 gene polymorphisms versus cardioimmunological responses in sudden infant death.Fetal Pediatr Pathol2008Perskvist NSkoglund KEdston EBäckström GLodestad IPalm U17709376PubMedSynergy between the RE-1 silencer of transcription and NFkappaB in the repression of the neurotransmitter gene TAC1 in human mesenchymal stem cells.J Biol Chem2007Greco SJSmirnov SVMurthy RGRameshwar Praphe nuclei neuronCL:0002610Cell Type19289301PubMedSNP association and sequence analysis of the NOS1AP gene in SIDS.Leg Med (Tokyo)2009Osawa MKimura RHasegawa IMukasa NSatoh F10197817PubMedReduction in choline acetyltransferase immunoreactivity but not muscarinic-m2 receptor immunoreactivity in the brainstem of SIDS infants.J Neuropathol Exp Neurol1999Mallard CTolcos MLeditschke JCampbell PRees S16728402PubMedGlucocorticoid and androgen activation of monoamine oxidase A is regulated differently by R1 and Sp1.J Biol Chem200616728402PubMedGlucocorticoid and androgen activation of monoamine oxidase A is regulated differently by R1 and Sp1.J Biol Chem200616728402PubMedGlucocorticoid and androgen activation of monoamine oxidase A is regulated differently by R1 and Sp1.J Biol Chem2006Ou XMChen KShih JC14693395PubMedThe correlation between microtubule-associated protein 2 in the brainstem of SIDS victims and physiological data on sleep apnea.Early Hum Dev2003Sawaguchi TPatricia FKadhim HGroswasser JSottiaux MNishida HKahn A22334710PubMedMicroRNA-130a represses transcriptional activity of aquaporin 4 M1 promoter.J Biol Chem2012Sepramaniam SYing LKArmugam AWintour EMJeyaseelan K19476549PubMedDynamic chromatin remodeling events in hippocampal neurons are associated with NMDA receptor-mediated activation of Bdnf gene promoter 1.J Neurochem2009Tian FHu XZWu XJiang HPan HMarini AMLipsky RH15758173PubMedA differentially autoregulated Pet-1 enhancer region is a critical target of the transcriptional cascade that governs serotonin neuron development.J Neurosci2005Scott MMKrueger KCDeneris ES18045290PubMed18045290PubMedPost-mortem analysis for two prevalent beta-oxidation mutations in sudden infant death.Pediatr Int2007Yang ZLantz PEIbdah JA21204411PubMedTranscriptional Regulation of NMDA Receptor Expression2009Bai GHoffman PW18041756PubMedCongenital central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death.Pediatr Pulmonol2008Gronli JOSantucci BALeurgans SEBerry-Kravis EMWeese-Mayer DE9038229PubMedTyrosine hydroxylase gene promoter activity is regulated by both cyclic AMP-responsive element and AP1 sites following calcium influx. Evidence for cyclic amp-responsive element binding protein-independent regulation.J Biol Chem1997Nagamoto-Combs KPiech KMBest JASun BTank AW21836131PubMedLoss-of-function mutations in the KCNJ8-encoded Kir6.1 K(ATP) channel and sudden infant death syndrome.Circ Cardiovasc Genet2011Tester DJTan BHMedeiros-Domingo ASong CMakielski JCAckerman MJ19342987PubMedSudden infant death syndrome and sudden intrauterine unexplained death: correlation between hypoplasia of raphé nuclei and serotonin transporter gene promoter polymorphism.Pediatr Res2009Lavezzi AMCasale VOneda RWeese-Mayer DEMatturri L15056938PubMed[The regulatory mechanism for neuron specific expression of PACAP gene]Nippon Yakurigaku Zasshi2004Miyata ASugawara HIwata SShimizu TKangawa K16830328PubMedSudden 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 EM21976671PubMedBrainstem deficiency of the 14-3-3 regulator of serotonin synthesis: a proteomics analysis in the sudden infant death syndrome.Mol Cell Proteomics2012Broadbelt KGRivera KDPaterson DSDuncan JRTrachtenberg FLPaulo JAStapels MDBorenstein NSBelliveau RAHaas EAStanley CKrous HFSteen HKinney HC19396608PubMedInterleukin-6 and the serotonergic system of the medulla oblongata in the sudden infant death syndrome.Acta Neuropathol2009Rognum IJHaynes RLVege AYang MRognum TOKinney HC19247214PubMedThe role of 5-HT3 and other excitatory receptors in central cardiorespiratory responses to hypoxia: implications for sudden infant death syndrome.Pediatr Res200919247214PubMedThe role of 5-HT3 and other excitatory receptors in central cardiorespiratory responses to hypoxia: implications for sudden infant death syndrome.Pediatr Res2009Dergacheva OKamendi HWang XPinol RMFrank JJameson HGorini CMendelowitz D9259266PubMedGenomic and mutational analysis of the mitochondrial trifunctional protein beta-subunit (HADHB) gene in patients with trifunctional protein deficiency.Hum Mol Genet1997Orii KEAoyama TWakui KFukushima YMiyajima HYamaguchi SOrii TKondo NHashimoto T17077377PubMed17077377PubMedMultiple serotonergic brainstem abnormalities in sudden infant death syndrome.JAMA2006Paterson DSTrachtenberg FLThompson EGBelliveau RABeggs AHDarnall RChadwick AEKrous HFKinney HC15918042PubMedIdentification of novel polymorphisms in the glucokinase and glucose-6-phosphatase genes in infants who died suddenly and unexpectedly.J Mol Med (Berl)2005Forsyth LHume RHowatson ABusuttil ABurchell A15584216PubMedRole of somatostatin and apoptosis in breathing control in sudden perinatal and infant unexplained death.Clin Neuropathol2004Lavezzi AMOttaviani GMatturri L18084013PubMedNeuronal cell death in the Sudden Infant Death Syndrome brainstem and associations with risk factors.Brain2008Machaalani RWaters KA17973628PubMedActivation and stabilization of human tryptophan hydroxylase 2 by phosphorylation and 14-3-3 binding.Biochem J2008Winge IMcKinney JAYing MD'Santos CSKleppe RKnappskog PMHaavik J17354259PubMedGenetic variation in hepatic glucose-6-phosphatase system genes in cases of sudden infant death syndrome.J Pathol2007Forsyth LScott HMHowatson ABusuttil AHume RBurchell A20124538PubMedBrainstem serotonergic deficiency in sudden infant death syndrome.JAMA2010Duncan JRPaterson DSHoffman JMMokler DJBorenstein NSBelliveau RAKrous HFHaas EAStanley CNattie EETrachtenberg FLKinney HC22351881PubMedAssociation between a functional polymorphism in the MAOA gene and sudden infant death syndrome.Pediatrics2012Klintschar MHeimbold C10421804PubMedLocalization of regulatory protein binding sites in the proximal region of human myometrial connexin 43 gene.Mol Hum Reprod1999Echetebu COAli MIzban MGMacKay LGarfield RE18234890PubMedBHLHB2 controls Bdnf promoter 4 activity and neuronal excitability.J Neurosci2008Jiang XTian FDu YCopeland NGJenkins NATessarollo LWu XPan HHu XZXu KKenney HEgan SETurley HHarris ALMarini AMLipsky RH17869437PubMed5-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 D18094064PubMedActivation of 5-HT1A receptors in medullary raphé disrupts sleep and decreases shivering during cooling in the conscious piglet.Am J Physiol Regul Integr Comp Physiol2008Brown JWSirlin EABenoit AMHoffman JMDarnall RA19958302PubMedCytokine gene polymorphisms and sudden infant death syndrome.Acta Paediatr2009Ferrante LOpdal SHVege ARognum TO19666841PubMedGPD1L links redox state to cardiac excitability by PKC-dependent phosphorylation of the sodium channel SCN5A.Am J Physiol Heart Circ Physiol2009Valdivia CRUeda KAckerman MJMakielski JC