Sudden infant death syndrome (SIDS) susceptibility pathways (Homo sapiens)

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79, 193532, 47, 514753563119445554853225353132242720222123, 29, 482155528383, 8315555538383163, 8383846385533255538283838338TR: Transcriptional RegulationPutative TRsOHHOSoma MembraneSleepHeartC825TNucleusFatty Liver (Hepatic steatosis) and SIDSNHSPhSIDS Susceptibility PathwaysTRrcircadianBradycardiaBrainrs2856966Gi signalingHNTRrOPutative TRPutative TRIVS-191_190insArs6295 (-1019)SIDS associated polymorphismsIncreased relative SIDS expressionIncreased long-QT with SIDSInfant (<1 year in age)Putative TRsCell MembraneMiscelaneous SIDS AssociatedOther2K+Putative TRs2Cardiac myocytePutative TRsdepressionPutative TRsPutative TRSPhNerve TerminalHNPutative TRDecreased relative SIDS expressionHOG5477AHNPutative TRsSPh+101A>GOHG-proteinPutative TRsmisc coding regionPutative TRsIncreased brainstem hypoplasia with SIDSSerotonin Synthesis and MetabolismGq signalingSerotonin SignalingFocal AdhesionsSPhNucleusGs signaling2+OPutative TROAssociated with Infection and SIDScAMPRapidly-activating Potassium CurrentNHVagal ToneSph: SIDS Phenotype Animal ModelOHPutative TR Slowly-Activating Potassium Current2 BrownAdiposeSPh4R/4RK+HNHOSerotonin producing raphe neuronCaPutative TRSerotonin Neuron SpecificationSarcoplasmic ReticulumNa+Other NeuronalThermoregulationNHG2989T64250422311361823393741243914SCN5ATPH2NFKB1SP1POU3F2SCN5A5-HTPKCNH2HTR1ANFYAVIPR2HADHACAV3KCNQ1VIPR1KCNH2 TPH2HTR2AADCYAP1ADCYAP1R1HTR1AGATA3RESTCDCA7LDEAF1RYR2RETIL10HES1TPH1CHRNA4FOXM1KCNQ1DDCECE1AVPPHOX2BRESTCREB1TPH15-HIAANKX3-1MAOAGATA2ARIL8ESR2ACADMSP1POU3F2TLX3HSPD1GNB3CTCFADCYAP1SLC6A4C4ARYR2Nicotine5-HTMAOAFEVCC2D1AYBX1EP300EN1PHOX2AIL6RRORAC4BASCL1SLC9A3L-Tryptophan5-HTFEVPPARGC1ANR3C1CHRNB2RESTDDCHES5CAV3NKX2-25-HTPPARGC1BLMX1BTNFIL6CHRNB4217531657194792630584353410495440, 4411745


Description

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).

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History

View all...
CompareRevisionActionTimeUserComment
134932view00:19, 30 July 2024EweitzStandardize case
134865view20:27, 27 July 2024EweitzOntology Term : 'serotonergic neuron' added !
134864view20:27, 27 July 2024EweitzOntology Term : 'brown adipocyte' added !
134863view20:24, 27 July 2024EweitzFix typo: "Miscelaneous" -> "Miscellaneous", omit redundant title
129309view13:49, 26 March 2024MkutmonOntology Term : 'disease pathway' added !
128759view13:07, 21 February 2024EweitzUpgrade disease node
124910view09:44, 31 December 2022EgonwOne last encoding issue
124909view09:19, 31 December 2022EgonwOne more fixed character encoding issue
124908view09:18, 31 December 2022EgonwFixed character encoding issues
124907view08:49, 31 December 2022EgonwConverted into a translation
117178view09:58, 18 May 2021EweitzModified title
113813view13:58, 26 November 2020Finterlysmall graphical update
106830view13:31, 17 September 2019MaintBotHMDB identifier normalization
105829view23:06, 15 August 2019Khanspersmodified description
101924view17:05, 17 November 2018EgonwRemoved whitespace in PubMed identifiers.
96990view11:22, 25 April 2018Fehrhartinteractions to graphical lines
96989view10:00, 25 April 2018Fehrhartinteractions to graphical lines
96988view09:55, 25 April 2018Fehrhartinteractions to graphical lines
96900view14:21, 18 April 2018FehrhartInteractions to graphical lines
96897view14:09, 18 April 2018FehrhartInteractions to graphical lines
96896view14:04, 18 April 2018FehrhartConverted interactions to graphical lines
96895view13:58, 18 April 2018FehrhartConverted interactions to graphical lines
92921view11:36, 17 July 2017EgonwReplaced a CAS of a salt with that of the parent compound.
86078view09:59, 29 June 2016MirellaKalafatiModified title
80056view09:31, 3 May 2015LarsEijssenCorrected spelling error: serotinergic -> serotonergic
78533view10:30, 7 January 2015MaintBotadded missing graphIds
74443view07:26, 20 April 2014EgonwFixed a PubMed ID.
73552view18:27, 30 January 2014EgonwH2O not H20....
70114view19:12, 12 July 2013MaintBotupdated to 2013 schema
68050view12:25, 29 June 2013EgonwFixed a few identifier issues.
68049view12:21, 29 June 2013EgonwFixed char encoding issues in references.
67641view11:43, 26 June 2013DdiglesOntology Term : 'serotonin signaling pathway' added !
59166view18:29, 22 February 2013MaintBotUpdated Ensembl data source
55364view18:39, 13 December 2012NsalomonisPeriodical save, work in progress
55358view18:18, 13 December 2012NsalomonisSpecify description
55355view18:08, 13 December 2012NsalomonisPeriodical save, work in progress
55354view17:58, 13 December 2012NsalomonisPeriodical save, work in progress
55353view17:47, 13 December 2012NsalomonisPeriodical save, work in progress
55352view17:32, 13 December 2012NsalomonisSpecify description
52941view21:29, 24 October 2012NsalomonisSpecify description
52817view01:50, 23 October 2012NsalomonisSpecify description
52816view00:16, 23 October 2012Nsalomonistest-without-DNA
52726view03:39, 20 October 2012NsalomonisSpecify description
52723view03:12, 20 October 2012NsalomonisSpecify description
52722view03:02, 20 October 2012NsalomonisSpecify description
52721view00:57, 20 October 2012NsalomonisSpecify description
52720view00:55, 20 October 2012NsalomonisSpecify description
52719view00:32, 20 October 2012NsalomonisSpecify description
52718view00:20, 20 October 2012NsalomonisSpecify description
52715view23:35, 19 October 2012NsalomonisSpecify description

External references

DataNodes

View all...
NameTypeDatabase referenceComment
5-HIAAMetaboliteHMDB00763 (HMDB)
5-HTMetaboliteHMDB00259 (HMDB)
5-HTPMetaboliteHMDB00472 (HMDB)
ACADMGeneProduct34 (Entrez Gene)
ADCYAP1GeneProduct116 (Entrez Gene)
ADCYAP1R1GeneProduct117 (Entrez Gene)
ARGeneProduct367 (Entrez Gene)
ASCL1GeneProduct429 (Entrez Gene)
AVPGeneProduct551 (Entrez Gene)
C4AGeneProduct720 (Entrez Gene)
C4BGeneProduct721 (Entrez Gene)
CAV3GeneProduct859 (Entrez Gene)
CC2D1AGeneProduct54862 (Entrez Gene)
CDCA7LGeneProduct55536 (Entrez Gene)
CHRNA4GeneProduct1137 (Entrez Gene)
CHRNB2GeneProduct1141 (Entrez Gene)
CHRNB4GeneProduct1143 (Entrez Gene)
CREB1GeneProduct1385 (Entrez Gene)
CTCFGeneProduct10664 (Entrez Gene)
DDCGeneProduct1644 (Entrez Gene)
DEAF1GeneProduct10522 (Entrez Gene)
ECE1GeneProduct1889 (Entrez Gene)
EN1GeneProduct2019 (Entrez Gene)
EP300GeneProduct2033 (Entrez Gene)
ESR2GeneProduct2100 (Entrez Gene)
FEVGeneProduct54738 (Entrez Gene)
FOXM1GeneProduct2305 (Entrez Gene)
GATA2GeneProduct2624 (Entrez Gene)
GATA3GeneProduct2625 (Entrez Gene)
GNB3GeneProduct2784 (Entrez Gene)
HADHAGeneProduct3030 (Entrez Gene)
HES1GeneProduct3280 (Entrez Gene)
HES5GeneProduct388585 (Entrez Gene)
HSPD1GeneProduct3329 (Entrez Gene)
HTR1AGeneProduct3350 (Entrez Gene)
HTR2AGeneProduct3356 (Entrez Gene)
IL10GeneProduct3586 (Entrez Gene)
IL6GeneProduct3569 (Entrez Gene)
IL6RGeneProduct3570 (Entrez Gene)
IL8GeneProduct3576 (Entrez Gene)
KCNH2 GeneProduct3757 (Entrez Gene)
KCNH2GeneProduct3757 (Entrez Gene)
KCNQ1GeneProduct3784 (Entrez Gene)
L-TryptophanMetaboliteHMDB00929 (HMDB)
LMX1BGeneProduct4010 (Entrez Gene)
MAOAGeneProduct4128 (Entrez Gene)
NFKB1GeneProduct4790 (Entrez Gene)
NFYAGeneProduct4800 (Entrez Gene)
NKX2-2GeneProduct4821 (Entrez Gene)
NKX3-1GeneProduct4824 (Entrez Gene)
NR3C1GeneProduct2908 (Entrez Gene)
NicotineMetaboliteHMDB01934 (HMDB)
PHOX2AGeneProduct401 (Entrez Gene)
PHOX2BGeneProduct8929 (Entrez Gene)
POU3F2GeneProduct5454 (Entrez Gene)
PPARGC1AGeneProduct10891 (Entrez Gene)
PPARGC1BGeneProduct133522 (Entrez Gene)
RESTGeneProduct5978 (Entrez Gene)
RETGeneProduct5979 (Entrez Gene)
RORAGeneProduct6095 (Entrez Gene)
RYR2GeneProduct6262 (Entrez Gene)
SCN5AGeneProduct6331 (Entrez Gene)
SLC6A4GeneProduct6532 (Entrez Gene) Contains an alternative promoter in the first and possibly second intron.
SLC9A3GeneProduct6550 (Entrez Gene)
SP1GeneProduct6667 (Entrez Gene)
TLX3GeneProduct30012 (Entrez Gene)
TNFGeneProduct7124 (Entrez Gene)
TPH1GeneProduct7166 (Entrez Gene)
TPH2GeneProduct121278 (Entrez Gene)
VIPR1GeneProduct7433 (Entrez Gene)
VIPR2GeneProduct7434 (Entrez Gene)
YBX1GeneProduct4904 (Entrez Gene)

Annotated Interactions

No annotated interactions

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