SIDS susceptibility pathways (WP1266)

Mus musculus

Open in new tab Open in Newt (SBGN)
Download PNG Download SVG Download JSON Download GPML Learn more about Downloads
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

last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.

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
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
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
C4A GeneProduct ncbigene:625018
Gata2 GeneProduct ncbigene:14461
Kcnh2 GeneProduct ncbigene:16511
Ddc GeneProduct ncbigene:13195
Cav3 GeneProduct ncbigene:12391
Avp GeneProduct ncbigene:11998
Adcyap1r1 GeneProduct ncbigene:11517
Ppargc1a GeneProduct ncbigene:19017
Ppargc1b GeneProduct ncbigene:170826
Lmx1b GeneProduct ncbigene:16917
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
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
Gnb3 GeneProduct ncbigene:14695
Ar GeneProduct ncbigene:11835
Foxm1 GeneProduct ncbigene:14235
Il6ra GeneProduct ncbigene:16194
Creb1 GeneProduct ncbigene:12912
KCNQ1 GeneProduct ncbigene:16535
Nr3c1 GeneProduct ncbigene:14815
Phox2a GeneProduct ncbigene:11859
Ret GeneProduct ncbigene:19713
Hes5 GeneProduct ncbigene:15208
Tlx3 GeneProduct ncbigene:27140
Nfkb1 GeneProduct ncbigene:18033
Nkx2-2 GeneProduct ncbigene:18088
Phox2b GeneProduct ncbigene:18935
Chrnb2 GeneProduct ncbigene:11444

References

  1. Vasopressin and autonomic mechanisms mediate cardiovascular actions of central serotonin. Pérgola PE, Alper RH. Am J Physiol. 1991 Jun;260(6 Pt 2):R1188-93. PubMed Europe PMC Scholia
  2. Cloning and characterization of the 5’-upstream regulatory region of the Ca(2+)-release channel gene of cardiac sarcoplasmic reticulum. Nishida K, Otsu K, Hori M, Kuzuya T, Tada M. Eur J Biochem. 1996 Sep 1;240(2):408–15. PubMed Europe PMC Scholia
  3. Human heat shock protein gene polymorphisms and sudden infant death syndrome. Rahim RA, Boyd PA, Ainslie Patrick WJ, Burdon RH. Arch Dis Child. 1996 Nov;75(5):451–2. PubMed Europe PMC Scholia
  4. Winged 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. Raynal JF, Dugast C, Le Van Thaï A, Weber MJ. Brain Res Mol Brain Res. 1998 May;56(1–2):227–37. PubMed Europe PMC Scholia
  5. CBF/NF-Y activates transcription of the human tryptophan hydroxylase gene through an inverted CCAAT box. Teerawatanasuk N, Carr LG. Brain Res Mol Brain Res. 1998 Mar 30;55(1):61–70. PubMed Europe PMC Scholia
  6. The complement component C4 in sudden infant death. Opdal SH, Vege A, Stave AK, Rognum TO. Eur J Pediatr. 1999 Mar;158(3):210–2. PubMed Europe PMC Scholia
  7. The ETS domain factor Pet-1 is an early and precise marker of central serotonin neurons and interacts with a conserved element in serotonergic genes. Hendricks T, Francis N, Fyodorov D, Deneris ES. J Neurosci. 1999 Dec 1;19(23):10348–56. PubMed Europe PMC Scholia
  8. Involvement of NF-Y and Sp1 in basal and cAMP-stimulated transcriptional activation of the tryptophan hydroxylase (TPH ) gene in the pineal gland. Côté F, Schussler N, Boularand S, Peirotes A, Thévenot E, Mallet J, et al. J Neurochem. 2002 May;81(4):673–85. PubMed Europe PMC Scholia
  9. Sudden neonatal death in PACAP-deficient mice is associated with reduced respiratory chemoresponse and susceptibility to apnoea. Cummings KJ, Pendlebury JD, Sherwood NM, Wilson RJA. J Physiol. 2004 Feb 15;555(Pt 1):15–26. PubMed Europe PMC Scholia
  10. Cooperative 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. Dugast-Darzacq C, Egloff S, Weber MJ. Brain Res Mol Brain Res. 2004 Jan 5;120(2):151–63. PubMed Europe PMC Scholia
  11. Cell type-dependent recruitment of trichostatin A-sensitive repression of the human 5-HT1A receptor gene. Lemonde S, Rogaeva A, Albert PR. J Neurochem. 2004 Feb;88(4):857–68. PubMed Europe PMC Scholia
  12. The regulatory mechanism for neuron specific expression of PACAP gene. Miyata A, Sugawara H, Iwata S ichi, Shimizu T, Kangawa K. Nihon Yakurigaku Zasshi. 2004 Apr;123(4):235–42. PubMed Europe PMC Scholia
  13. RORalpha regulates the expression of genes involved in lipid homeostasis in skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of ROR. Lau P, Nixon SJ, Parton RG, Muscat GEO. J Biol Chem. 2004 Aug 27;279(35):36828–40. PubMed Europe PMC Scholia
  14. Sudden infant death syndrome: case-control frequency differences at genes pertinent to early autonomic nervous system embryologic development. Weese-Mayer DE, Berry-Kravis EM, Zhou L, Maher BS, Curran ME, Silvestri JM, et al. Pediatr Res. 2004 Sep;56(3):391–5. PubMed Europe PMC Scholia
  15. A differentially autoregulated Pet-1 enhancer region is a critical target of the transcriptional cascade that governs serotonin neuron development. Scott MM, Krueger KC, Deneris ES. J Neurosci. 2005 Mar 9;25(10):2628–36. PubMed Europe PMC Scholia
  16. Transcriptional 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. Fukuchi M, Tabuchi A, Tsuda M. J Pharmacol Sci. 2005 Jul;98(3):212–8. PubMed Europe PMC Scholia
  17. PHOX2B regulates its own expression by a transcriptional auto-regulatory mechanism. Cargnin F, Flora A, Di Lascio S, Battaglioli E, Longhi R, Clementi F, et al. J Biol Chem. 2005 Nov 11;280(45):37439–48. PubMed Europe PMC Scholia
  18. Increased serotonin receptor availability in human sleep: evidence from an [18F]MPPF PET study in narcolepsy. Derry C, Benjamin C, Bladin P, le Bars D, Tochon-Danguy H, Berkovic SF, et al. Neuroimage. 2006 Apr 1;30(2):341–8. PubMed Europe PMC Scholia
  19. Cell-specific repressor or enhancer activities of Deaf-1 at a serotonin 1A receptor gene polymorphism. Czesak M, Lemonde S, Peterson EA, Rogaeva A, Albert PR. J Neurosci. 2006 Feb 8;26(6):1864–71. PubMed Europe PMC Scholia
  20. Glucocorticoid and androgen activation of monoamine oxidase A is regulated differently by R1 and Sp1. Ou XM, Chen K, Shih JC. J Biol Chem. 2006 Jul 28;281(30):21512–25. PubMed Europe PMC Scholia
  21. Sudden infant death syndrome: Case-control frequency differences in paired like homeobox (PHOX) 2B gene. Rand CM, Weese-Mayer DE, Zhou L, Maher BS, Cooper ME, Marazita ML, et al. Am J Med Genet A. 2006 Aug 1;140(15):1687–91. PubMed Europe PMC Scholia
  22. The G protein beta3 subunit 825C allele is associated with sudden infant death due to infection. Hauge Opdal S, Melien Ø, Rootwelt H, Vege A, Arnestad M, Ole Rognum T. Acta Paediatr. 2006 Sep;95(9):1129–32. PubMed Europe PMC Scholia
  23. Multiple serotonergic brainstem abnormalities in sudden infant death syndrome. Paterson DS, Trachtenberg FL, Thompson EG, Belliveau RA, Beggs AH, Darnall R, et al. JAMA. 2006 Nov 1;296(17):2124–32. PubMed Europe PMC Scholia
  24. Specification and differentiation of serotonergic neurons. Alenina N, Bashammakh S, Bader M. Stem Cell Rev. 2006;2(1):5–10. PubMed Europe PMC Scholia
  25. Overexpression HERG K(+) channel gene mediates cell-growth signals on activation of oncoproteins SP1 and NF-kappaB and inactivation of tumor suppressor Nkx3.1. Lin H, Xiao J, Luo X, Wang H, Gao H, Yang B, et al. J Cell Physiol. 2007 Jul;212(1):137–47. PubMed Europe PMC Scholia
  26. Differential 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. Roberts J, Scott AC, Howard MR, Breen G, Bubb VJ, Klenova E, et al. J Neurosci. 2007 Mar 14;27(11):2793–801. PubMed Europe PMC Scholia
  27. A mechanism for sudden infant death syndrome (SIDS): stress-induced leak via ryanodine receptors. Tester DJ, Dura M, Carturan E, Reiken S, Wronska A, Marks AR, et al. Heart Rhythm. 2007 Jun;4(6):733–9. PubMed Europe PMC Scholia
  28. Characterization of a functional promoter polymorphism of the human tryptophan hydroxylase 2 gene in serotonergic raphe neurons. Scheuch K, Lautenschlager M, Grohmann M, Stahlberg S, Kirchheiner J, Zill P, et al. Biol Psychiatry. 2007 Dec 1;62(11):1288–94. PubMed Europe PMC Scholia
  29. Sudden infant death syndrome: rare mutation in the serotonin system FEV gene. Rand CM, Berry-Kravis EM, Zhou L, Fan W, Weese-Mayer DE. Pediatr Res. 2007 Aug;62(2):180–2. PubMed Europe PMC Scholia
  30. Regulation of tryptophan hydroxylase-2 gene expression by a bipartite RE-1 silencer of transcription/neuron restrictive silencing factor (REST/NRSF) binding motif. Patel PD, Bochar DA, Turner DL, Meng F, Mueller HM, Pontrello CG. J Biol Chem. 2007 Sep 14;282(37):26717–24. PubMed Europe PMC Scholia
  31. 5-HT(2) receptor subtypes mediate different long-term changes in GABAergic activity to parasympathetic cardiac vagal neurons in the nucleus ambiguus. Dergacheva O, Griffioen KJS, Wang X, Kamendi H, Gorini C, Mendelowitz D. Neuroscience. 2007 Nov 9;149(3):696–705. PubMed Europe PMC Scholia
  32. NF-kappaB-dependent transcriptional regulation of the cardiac scn5a sodium channel by angiotensin II. Shang LL, Sanyal S, Pfahnl AE, Jiao Z, Allen J, Liu H, et al. Am J Physiol Cell Physiol. 2008 Jan;294(1):C372-9. PubMed Europe PMC Scholia
  33. Congenital central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death. Gronli JO, Santucci BA, Leurgans SE, Berry-Kravis EM, Weese-Mayer DE. Pediatr Pulmonol. 2008 Jan;43(1):77–86. PubMed Europe PMC Scholia
  34. Activation of 5-HT1A receptors in medullary raphé disrupts sleep and decreases shivering during cooling in the conscious piglet. Brown JW, Sirlin EA, Benoit AM, Hoffman JM, Darnall RA. Am J Physiol Regul Integr Comp Physiol. 2008 Mar;294(3):R884-94. PubMed Europe PMC Scholia
  35. Genomic structure, transcriptional control, and tissue distribution of HERG1 and KCNQ1 genes. Luo X, Xiao J, Lin H, Lu Y, Yang B, Wang Z. Am J Physiol Heart Circ Physiol. 2008 Mar;294(3):H1371-80. PubMed Europe PMC Scholia
  36. Genetic variation in the HTR1A gene and sudden infant death syndrome. Morley ME, Rand CM, Berry-Kravis EM, Zhou L, Fan W, Weese-Mayer DE. Am J Med Genet A. 2008 Apr 1;146A(7):930–3. PubMed Europe PMC Scholia
  37. TNF-alpha promoter polymorphisms in sudden infant death. Ferrante L, Opdal SH, Vege A, Rognum TO. Hum Immunol. 2008 Jun;69(6):368–73. PubMed Europe PMC Scholia
  38. TNF-alpha and IL-10 gene polymorphisms versus cardioimmunological responses in sudden infant death. Perskvist N, Skoglund K, Edston E, Bäckström G, Lodestad I, Palm U. Fetal Pediatr Pathol. 2008;27(3):149–65. PubMed Europe PMC Scholia
  39. Transcriptional regulation at a HTR1A polymorphism associated with mental illness. Le François B, Czesak M, Steubl D, Albert PR. Neuropharmacology. 2008 Nov;55(6):977–85. PubMed Europe PMC Scholia
  40. PHOX2B mutations and ventilatory control. Gallego J, Dauger S. Respir Physiol Neurobiol. 2008 Dec 10;164(1–2):49–54. PubMed Europe PMC Scholia
  41. HTR2A variation and sudden infant death syndrome: a case-control analysis. Rand CM, Berry-Kravis EM, Fan W, Weese-Mayer DE. Acta Paediatr. 2009 Jan;98(1):58–61. PubMed Europe PMC Scholia
  42. Chronic effect of nicotine on serotonin transporter mRNA in the raphe nucleus of rats: reversal by co-administration of bupropion. Semba J, Wakuta M. Psychiatry Clin Neurosci. 2008 Aug;62(4):435–41. PubMed Europe PMC Scholia
  43. Association of dopamine transporter and monoamine oxidase molecular polymorphisms with sudden infant death syndrome and stillbirth: new insights into the serotonin hypothesis. Filonzi L, Magnani C, Lavezzi AM, Rindi G, Parmigiani S, Bevilacqua G, et al. Neurogenetics. 2009 Feb;10(1):65–72. PubMed Europe PMC Scholia
  44. Cardiomyopathic and channelopathic causes of sudden unexplained death in infants and children. Tester DJ, Ackerman MJ. Annu Rev Med. 2009;60:69–84. PubMed Europe PMC Scholia
  45. Sudden infant death syndrome (SIDS) in African Americans: polymorphisms in the gene encoding the stress peptide pituitary adenylate cyclase-activating polypeptide (PACAP). Cummings KJ, Klotz C, Liu WQ, Weese-Mayer DE, Marazita ML, Cooper ME, et al. Acta Paediatr. 2009 Mar;98(3):482–9. PubMed Europe PMC Scholia
  46. Positron emission tomography quantification of serotonin-1A receptor binding in medication-free bipolar depression. Sullivan GM, Ogden RT, Oquendo MA, Kumar JSD, Simpson N, Huang Y yu, et al. Biol Psychiatry. 2009 Aug 1;66(3):223–30. PubMed Europe PMC Scholia
  47. Sudden infant death syndrome and sudden intrauterine unexplained death: correlation between hypoplasia of raphé nuclei and serotonin transporter gene promoter polymorphism. Lavezzi AM, Casale V, Oneda R, Weese-Mayer DE, Matturri L. Pediatr Res. 2009 Jul;66(1):22–7. PubMed Europe PMC Scholia
  48. Severe spontaneous bradycardia associated with respiratory disruptions in rat pups with fewer brain stem 5-HT neurons. Cummings KJ, Commons KG, Fan KC, Li A, Nattie EE. Am J Physiol Regul Integr Comp Physiol. 2009 Jun;296(6):R1783-96. PubMed Europe PMC Scholia
  49. Interleukin-6 and the serotonergic system of the medulla oblongata in the sudden infant death syndrome. Rognum IJ, Haynes RL, Vege A, Yang M, Rognum TO, Kinney HC. Acta Neuropathol. 2009 Oct;118(4):519–30. PubMed Europe PMC Scholia