SIDS susceptibility pathways (WP1266)

Mus musculus

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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).

Authors

Egon Willighagen , Daniela Digles , and Eric Weitz

Activity

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Organisms

Mus musculus

Communities

Annotations

Pathway Ontology

serotonin signaling pathway

Disease Ontology

sudden infant death syndrome

Participants

Label Type Compact URI Comment
5-HT Metabolite hmdb:HMDB0000259
L-Tryptophan Metabolite hmdb:HMDB0000929
Nicotine Metabolite hmdb:HMDB0001934
5-HTP Metabolite hmdb:HMDB0000472
5-HT Metabolite hmdb:HMDB0000259
5-HT Metabolite hmdb:HMDB0000259
Scn5a GeneProduct ncbigene:20271
Adcyap1 GeneProduct ncbigene:11516
Il10 GeneProduct ncbigene:16153
Tph1 GeneProduct ncbigene:21990
Maoa GeneProduct ncbigene:17161
Sp1 GeneProduct ncbigene:20683
Hes1 GeneProduct ncbigene:15205
C4B GeneProduct ncbigene:12268
Rest GeneProduct ncbigene:19712
Htr1a GeneProduct ncbigene:15550
Cc2d1a GeneProduct ncbigene:212139
Tph1 GeneProduct ncbigene:21990
Ctcf GeneProduct ncbigene:13018
Nkx3-1 GeneProduct ncbigene:18095
Ryr2 GeneProduct ncbigene:20191
Chrnb4 GeneProduct ncbigene:108015
Tnf GeneProduct ncbigene:21926
Ep300 GeneProduct ncbigene:328572
Rest GeneProduct ncbigene:19712
C4A GeneProduct ncbigene:625018
Gata2 GeneProduct ncbigene:14461
Kcnh2 GeneProduct ncbigene:16511
Ddc GeneProduct ncbigene:13195
Cav3 GeneProduct ncbigene:12391
Cav3 GeneProduct ncbigene:12391
Avp GeneProduct ncbigene:11998
Adcyap1r1 GeneProduct ncbigene:11517
Ppargc1a GeneProduct ncbigene:19017
Ppargc1b GeneProduct ncbigene:170826
Lmx1b GeneProduct ncbigene:16917
Scn5a GeneProduct ncbigene:20271
Chrna4 GeneProduct ncbigene:11438
Nfya GeneProduct ncbigene:18044
Kcnq1 GeneProduct ncbigene:16535
Ascl1 GeneProduct ncbigene:17172
Rora GeneProduct ncbigene:19883
Deaf1 GeneProduct ncbigene:54006
Htr2a GeneProduct ncbigene:15558
Adcyap1 GeneProduct ncbigene:11516
Vipr2 GeneProduct ncbigene:22355
En1 GeneProduct ncbigene:13798
Il6 GeneProduct ncbigene:16193
Ybx1 GeneProduct ncbigene:22608
Gata3 GeneProduct ncbigene:14462
Vipr1 GeneProduct ncbigene:22354
Tph2 GeneProduct ncbigene:216343
Slc6a4 GeneProduct ncbigene:15567 Contains an alternative promoter in the first and possibly second intron.
Cdca7l GeneProduct ncbigene:217946
Hspd1 GeneProduct ncbigene:15510
Pou3f2 GeneProduct ncbigene:18992
Fev GeneProduct ncbigene:260298
Ece1 GeneProduct ncbigene:230857
Pou3f2 GeneProduct ncbigene:18992
Gnb3 GeneProduct ncbigene:14695
Maoa GeneProduct ncbigene:17161
Ar GeneProduct ncbigene:11835
Ddc GeneProduct ncbigene:13195
Foxm1 GeneProduct ncbigene:14235
Il6ra GeneProduct ncbigene:16194
Creb1 GeneProduct ncbigene:12912
Tph2 GeneProduct ncbigene:216343
Htr1a GeneProduct ncbigene:15550
KCNQ1 GeneProduct ncbigene:16535
Nr3c1 GeneProduct ncbigene:14815
Phox2a GeneProduct ncbigene:11859
Ret GeneProduct ncbigene:19713
Sp1 GeneProduct ncbigene:20683
Hes5 GeneProduct ncbigene:15208
Ryr2 GeneProduct ncbigene:20191
Tlx3 GeneProduct ncbigene:27140
Nfkb1 GeneProduct ncbigene:18033
Nkx2-2 GeneProduct ncbigene:18088
Phox2b GeneProduct ncbigene:18935
Rest GeneProduct ncbigene:19712
Fev GeneProduct ncbigene:260298
Chrnb2 GeneProduct ncbigene:11444

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