Sudden infant death syndrome (SIDS) susceptibility pathways (WP706)

Homo sapiens

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 ( 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 ( Proteins on this pathway have targeted assays available via the [ CPTAC Assay Portal].


Nathan Salomonis , Alex Pico , Kristina Hanspers , Daniela Digles , Egon Willighagen , Lars Eijssen , Marianthi Kalafati , Friederike Ehrhart , Finterly Hu , Eric Weitz , and Martina Summer-Kutmon


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Homo sapiens




Pathway Ontology

disease pathway serotonin signaling pathway

Cell Type Ontology

cardiac muscle cell raphe nuclei neuron

Disease Ontology

sudden infant death syndrome


Label Type Compact URI Comment
5-HT Metabolite hmdb:HMDB0000259
L-Tryptophan Metabolite hmdb:HMDB0000929
Nicotine Metabolite hmdb:HMDB0001934
Fluoxetine Metabolite cas:54910-89-3
5-HTP Metabolite hmdb:HMDB0000472
5-HIAA Metabolite hmdb:HMDB0000763
5-HT Metabolite hmdb:HMDB0000259
5-HT Metabolite hmdb:HMDB0000259
GABA Metabolite hmdb:HMDB0000112
5-HT Metabolite hmdb:HMDB0000259
Glutamate Metabolite hmdb:HMDB0004135
Dopamine Metabolite cas:62-31-7
Phenylalanine Metabolite cas:63-91-2
L-DOPA Metabolite cas:59-92-7
Acetylcholine Metabolite cas:51-84-3
Choline Metabolite cas:62-49-7
Tyrosine Metabolite cas:60-18-4
Glutamate Metabolite hmdb:HMDB0004135
Glutamate Metabolite hmdb:HMDB0004135
SCN5A GeneProduct ncbigene:6331
TACR1 GeneProduct ensembl:ENSG00000115353
ADCYAP1 GeneProduct ncbigene:116
ALDOA GeneProduct ensembl:ENSG00000149925
IL10 GeneProduct ncbigene:3586
TPH1 GeneProduct ncbigene:7166
CREB1 GeneProduct ensembl:ENSG00000118260
MAZ GeneProduct ensembl:ENSG00000103495
SSTR2 GeneProduct ensembl:ENSG00000180616
MAOA GeneProduct ncbigene:4128
NR3C1 GeneProduct ensembl:ENSG00000113580
SP1 GeneProduct ncbigene:6667
HES1 GeneProduct ncbigene:3280
ACADM GeneProduct ncbigene:34
C4B GeneProduct ncbigene:721
REST GeneProduct ncbigene:5978
HTR1A GeneProduct ncbigene:3350
CC2D1A GeneProduct ncbigene:54862
NFKB1 GeneProduct ensembl:ENSG00000109320
CREB1 GeneProduct ensembl:ENSG00000118260
TPH1 GeneProduct ncbigene:7166
CTCF GeneProduct ncbigene:10664
NKX3-1 GeneProduct ncbigene:4824
HADHA GeneProduct ncbigene:3030
RYR2 GeneProduct ncbigene:6262
CHRNB4 GeneProduct ncbigene:1143
TNF GeneProduct ncbigene:7124
EP300 GeneProduct ncbigene:2033
MEF2C GeneProduct ensembl:ENSG00000081189
REST GeneProduct ncbigene:5978
NGF GeneProduct ensembl:ENSG00000134259
MIR16-1 GeneProduct ncbigene:406950
PLP1 GeneProduct ensembl:ENSG00000123560
C4A GeneProduct ncbigene:720
MIR13A GeneProduct ensembl:ENSG00000208009
RUNX3 GeneProduct ensembl:ENSG00000020633
NEUROD1 GeneProduct ensembl:ENSG00000162992
HIF1A GeneProduct ensembl:ENSG00000100644
DLX2 GeneProduct ensembl:ENSG00000115844
JUN GeneProduct ensembl:ENSG00000177606
GATA2 GeneProduct ncbigene:2624
MIR210 GeneProduct ensembl:ENSG00000199038
CREBBP GeneProduct ensembl:ENSG00000005339
KCNH2 GeneProduct ncbigene:3757
DDC GeneProduct ncbigene:1644
SP3 GeneProduct ensembl:ENSG00000172845
CAV3 GeneProduct ncbigene:859
IL8 GeneProduct ncbigene:3576
CAV3 GeneProduct ncbigene:859
AVP GeneProduct ncbigene:551
ADCYAP1R1 GeneProduct ncbigene:117
PPARGC1A GeneProduct ncbigene:10891
THRB GeneProduct ensembl:ENSG00000151090
PPARGC1B GeneProduct ncbigene:133522
REST GeneProduct ensembl:ENSG00000084093
LMX1B GeneProduct ncbigene:4010
HES1 GeneProduct ensembl:ENSG00000114315
CHRNA4 GeneProduct ncbigene:1137
KCNH2 GeneProduct ncbigene:3757
NFYA GeneProduct ncbigene:4800
KCNQ1 GeneProduct ncbigene:3784
ASCL1 GeneProduct ncbigene:429
ESR2 GeneProduct ncbigene:2100
REST GeneProduct ensembl:ENSG00000084093
BHLHE40 GeneProduct ensembl:ENSG00000134107
RORA GeneProduct ncbigene:6095
DEAF1 GeneProduct ncbigene:10522
HTR2A GeneProduct ncbigene:3356
SP1 GeneProduct ensembl:ENSG00000185591
ADCYAP1 GeneProduct ncbigene:116
VIPR2 GeneProduct ncbigene:7434
EN1 GeneProduct ncbigene:2019
TCF3 GeneProduct ensembl:ENSG00000071564
IL6 GeneProduct ncbigene:3569
YBX1 GeneProduct ncbigene:4904
GATA3 GeneProduct ncbigene:2625
VIPR1 GeneProduct ncbigene:7433
SP1 GeneProduct ensembl:ENSG00000185591
TPH2 GeneProduct ncbigene:121278
SLC6A4 GeneProduct ncbigene:6532 Contains an alternative promoter in the first and possibly second intron.
TP73 GeneProduct ensembl:ENSG00000078900
CDCA7L GeneProduct ncbigene:55536
HSPD1 GeneProduct ncbigene:3329
POU3F2 GeneProduct ncbigene:5454
FEV GeneProduct ncbigene:54738
SSTR1 GeneProduct ensembl:ENSG00000139874
ECE1 GeneProduct ncbigene:1889
POU3F2 GeneProduct ncbigene:5454
GNB3 GeneProduct ncbigene:2784
MAOA GeneProduct ncbigene:4128
PKNOX1 GeneProduct ensembl:ENSG00000160199
AR GeneProduct ncbigene:367
DDC GeneProduct ncbigene:1644
PBX1 GeneProduct ensembl:ENSG00000185630
FOXM1 GeneProduct ncbigene:2305
IL6R GeneProduct ncbigene:3570
CREB1 GeneProduct ncbigene:1385
TPH2 GeneProduct ncbigene:121278
HTR1A GeneProduct ncbigene:3350
KCNQ1 GeneProduct ncbigene:3784
NR3C1 GeneProduct ncbigene:2908
PHOX2A GeneProduct ncbigene:401
RET GeneProduct ncbigene:5979
SP1 GeneProduct ncbigene:6667
HES5 GeneProduct ncbigene:388585
RYR2 GeneProduct ncbigene:6262
TLX3 GeneProduct ncbigene:30012
NFKB1 GeneProduct ncbigene:4790
NKX2-2 GeneProduct ncbigene:4821
EGR1 GeneProduct ensembl:ENSG00000120738
PHOX2B GeneProduct ncbigene:8929
REST GeneProduct ncbigene:5978
FEV GeneProduct ncbigene:54738
SP1 GeneProduct ensembl:ENSG00000185591
HIF1A GeneProduct ensembl:ENSG00000100644
CTNNB1 GeneProduct ensembl:ENSG00000168036
SOX2 GeneProduct ensembl:ENSG00000181449
NANOG GeneProduct ensembl:ENSG00000111704
POU5F1 GeneProduct ensembl:ENSG00000204531
BDNF GeneProduct ensembl:ENSG00000176697
NTRK2 GeneProduct ncbigene:4915
GABRA1 GeneProduct ncbigene:2554
CHRM2 GeneProduct ncbigene:1129
GJA1 GeneProduct ensembl:ENSG00000152661
SNTA1 GeneProduct ncbigene:6640
KCNJ8 GeneProduct ncbigene:3764
GJA1 GeneProduct ensembl:ENSG00000152661
PRKAR2B GeneProduct ncbigene:5577
YWHAE GeneProduct ncbigene:7531
YWHAZ GeneProduct ncbigene:7534 PMID: 9861170 PMID: 1317796
PRKAR1B GeneProduct ncbigene:5575
PRKAR2A GeneProduct ncbigene:5576
YWHAQ GeneProduct ncbigene:10971
YWHAG GeneProduct ncbigene:7532
PRKAR1A GeneProduct ncbigene:5573 KAP0 HUMAN
YWHAH GeneProduct ncbigene:7533
YWHAB GeneProduct ncbigene:7529
PRKACB GeneProduct ncbigene:5567
PRKACA GeneProduct ncbigene:5566
SLC9A3 GeneProduct ncbigene:6550
CASP3 GeneProduct ensembl:ENSG00000164305
FMO3 GeneProduct ensembl:ENSG00000007933
G6PC GeneProduct ensembl:ENSG00000131482
GCK GeneProduct ensembl:ENSG00000106633
GPD1L GeneProduct ensembl:ENSG00000152642
GRIN1 GeneProduct ensembl:ENSG00000176884
HADHB GeneProduct ensembl:ENSG00000138029
HTR3A GeneProduct ensembl:ENSG00000166736
SCN3B GeneProduct ensembl:ENSG00000166257
SCN4B GeneProduct ensembl:ENSG00000177098
SST GeneProduct ensembl:ENSG00000157005
AQP4 GeneProduct ensembl:ENSG00000171885
CPT1A GeneProduct ensembl:ENSG00000110090
IL1A GeneProduct ensembl:ENSG00000115008
IL1B GeneProduct ensembl:ENSG00000125538
IL1RN GeneProduct ensembl:ENSG00000136689
IL13 GeneProduct ensembl:ENSG00000169194
TSPYL1 GeneProduct ensembl:ENSG00000189241
VEGFA GeneProduct ensembl:ENSG00000112715
SCN5A GeneProduct ncbigene:6331
CHAT GeneProduct ensembl:ENSG00000070748
PAH GeneProduct ncbigene:5053
TH GeneProduct ensembl:ENSG00000180176
DDC GeneProduct ncbigene:1644
NOS1AP GeneProduct ensembl:ENSG00000198929
MAP2 GeneProduct ensembl:ENSG00000078018
TAC1 GeneProduct ensembl:ENSG00000006128
SLC1A3 GeneProduct ensembl:ENSG00000079215
SLC25A4 GeneProduct ensembl:ENSG00000151729
SNAP25 GeneProduct ensembl:ENSG00000132639
SST GeneProduct ensembl:ENSG00000157005
TAC1 GeneProduct ensembl:ENSG00000006128
HTR3A GeneProduct ensembl:ENSG00000166736
TH GeneProduct ensembl:ENSG00000180176
CHAT GeneProduct ensembl:ENSG00000070748
SLC9A3 GeneProduct ncbigene:6550
BDNF GeneProduct ensembl:ENSG00000176697
NTRK2 GeneProduct ncbigene:4915
AQP4 GeneProduct ensembl:ENSG00000171885
GRIN1 GeneProduct ensembl:ENSG00000176884
SP1 GeneProduct ensembl:ENSG00000185591
NFKB2 GeneProduct ensembl:ENSG00000077150
JUN GeneProduct ensembl:ENSG00000177606
HDAC9 GeneProduct ensembl:ENSG00000048052
MYB GeneProduct ensembl:ENSG00000118513
CEBPB GeneProduct ensembl:ENSG00000172216
SNTA1 GeneProduct ncbigene:6640
GPD1L GeneProduct ensembl:ENSG00000152642
SP1 GeneProduct ensembl:ENSG00000185591
JUN GeneProduct ensembl:ENSG00000177606
NR3C1 GeneProduct ensembl:ENSG00000113580
REST GeneProduct ensembl:ENSG00000084093
JUN GeneProduct ensembl:ENSG00000177606
CREB1 GeneProduct ensembl:ENSG00000118260
POU2F2 GeneProduct ensembl:ENSG00000028277
CREM GeneProduct ensembl:ENSG00000095794
REST GeneProduct ensembl:ENSG00000084093
NFKB1 GeneProduct ensembl:ENSG00000109320
CHRNB2 GeneProduct ncbigene:1141
CHRNA7 GeneProduct ensembl:ENSG00000175344
HDAC1 GeneProduct ensembl:ENSG00000116478
MBD1 GeneProduct ensembl:ENSG00000141644
MECP2 GeneProduct ensembl:ENSG00000169057
NFKB1 GeneProduct ensembl:ENSG00000109320
CREBBP GeneProduct ensembl:ENSG00000005339
GABRA1 GeneProduct ncbigene:2554
CREB1 GeneProduct ensembl:ENSG00000118260
VAMP2 GeneProduct ensembl:ENSG00000220205
TPPP GeneProduct ensembl:ENSG00000171368
ATP1A3 GeneProduct ensembl:ENSG00000105409
GAPDH GeneProduct ensembl:ENSG00000111640
HSP90B1 GeneProduct ensembl:ENSG00000166598
TF GeneProduct ensembl:ENSG00000091513
SPTBN1 GeneProduct ensembl:ENSG00000115306
YWHAG GeneProduct ensembl:ENSG00000170027
HIF1A GeneProduct ensembl:ENSG00000100644


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