Prader-Willi and Angelman Syndrome (Homo sapiens)

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16166, 2016AS ICGABA(A) receptorsubunit gammaGABA(A) receptorsubunit rhoFollicle stimulating hormonePathwayGene productMetabolites14HypersensitivebehaviourCleft palateEpilepsyTranscription of INK4/ARF locusMelanocytesRB signallingPWS regionLuteinizing hormoneStem cell differentiationGABA(A) receptorBreakpoint 3telomereAS regionBreakpoint 2centromereBreakpoint 1Non-imprintedSignaling pathway in GlioblastomaSLC45A2GABA(A) receptorsubunit deltaHERC2G2/M arrestCCND1LHBMDM4ARFL-dopaquinoneFSHBCCND2Melanin biosynthesisGABA(A) receptor subunit beta-3RB1p16-INK4aCDKN2BCDC6NK3RKISS1P-proteinG1/S progressionCGAApoptosisTyrosinasep53L-tyrosineMDM2CDK4NKB8, 9E2F1GABA(A) receptor subunit alpha-5IPWSNORD116@17OCA2MAGEL26, 11-13CYFIP1GABRA5GABRB314, 16Peptide hormone biosynthesisGHRH (1-108)GHRH (32-75)PCSK1TUBGCP5NHLH2Insulin (25-110)3, 17POMC (1-241)Oxytocin-neurophysin 1 (1-125)Ca2+GABRG3Ghrelin (24-51)SNORD115@18NIPA2GNRH1 (24-92)POMC (138-150)NIPA1Spliceosomal A complexATP10ASNORD107mRNA processingMajor splicing pathwayInsulin B chain(25-54)Synthesis, secretion and deacylation of ghrelinInsulin processingSNURFPWRN1GNRH1 (24-33)SNRPNNDN1, 6, 15UBE3A19BDNF (1-247)MKRN39NPAP1SNORD64SNORD109ASNORD109BNon-imprintedPWS ICOxytocin (20-28)BDNF (129-247)Ghrelin (1-117)SNURF-SNRPN4Spliceosomal E complexPCSK1Insulin A chain(90-110)Insulin (57-87)MKRN39GNRH1 (24-33)CGAUBE3A19E2F1UBE3Ap16-INK4aCDKN2CCCND1CCND2CDK6E2F1Signaling pathway in GlioblastomaGABRB3GABRA5OCA216GABRG311, 131215151, 665, 6Molecular motor kinesinDynein microtubule based molecular motorDevelopment of hypothalamic anorexigenic circuitsLeptin mediated depolarisation of POMC neuronsDNA transcriptionAxonal transportFormation of centrosomalmicrotubule organising centreMSX1DLX5MAGEL2FEZ2Proteasome degradationpathwayNDNPCM1FEZ1BBS4Neurite/axonal outgrowth1066Neurite outgrowthNGF6FEZ1PRKCZ6BBS4GNRH1181818Alternate splicing7, 18Full-length 5HT2C receptorsAdenosine-to-inosineRNA-editing2, 185'-...CGGUAUGUAGCAAUACGUAAUCCUAUUGAGCAUAGCC...-3'SNORD115HTR2C pre-mRNA3'-...GAGUCGCAUUAGGAUAACUCGUACUAA...-5'HTR2C mRNAExon IHTR2CSNORD115@18IIIIIIVVaVbVI14mim-stimulation:Gene expression or another process is stimulated by the indicated componentGene or gene productmim-binding: Binding of two indicated componentsmim-conversion: Conversion of one component into another (e.g. prohormone - hormone)mim-catalysation:The indicated component catalyses the reaction that is pointed atmim-inhibition:Gene expression or another process is inhibited by the indicated componentmim-transcription-translation:Stimulation of the indicated component results in transcription/translation of the following productsmim-cleavage:The indicated component or pathway causes the following component or complex to breakBasic arrow:The exact nature of the reaction is unknownAny arrow with dashed line:There might be multiple steps involved between the two indicated components,but the result is as indicated with the arrowmim-gap - dashed line:There is no indication of what process follows the expression of this componentSmall molecule, chemical or metaboliteRefers to an existing pathway that is involvedSpecifies a protein and the position in the full-length protein of the part involved here Protein (138-150)Any arrow coloured grey:The result of the interaction is as indicated with the arrow, but strong evidence for this reaction is lackingGABRR1GABRR2GABRR3GABRG2GABRG1GABRG3GABA(A) receptorsubunit rhoGABA(A) receptorsubunit gamma


Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are diseases that are both caused by a deletion in the same region of chromosome 15, namely 15q11-q13. Due to methylation patterns however, different genes are responsible for the two syndromes. This pathway depicts the currently known downstream molecular interactions of several of the genes involved in PWS and/or AS.

The colours of the pathway sections correspond to the colours of the genes on top. Dashed lines indicate a gap between a component and the downstream pathway. A rectangle is drawn to improve the clarity of the pathway; darker colours indicate that this particular part is derived from research in other animals than humans.

A detailed description of the pathway has been published by Ehrhart et al..

Proteins on this pathway have targeted assays available via the CPTAC Assay Portal

Quality Tags

Ontology Terms



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  1. Kuroda S, Nakagawa N, Tokunaga C, Tatematsu K, Tanizawa K; ''Mammalian homologue of the Caenorhabditis elegans UNC-76 protein involved in axonal outgrowth is a protein kinase C zeta-interacting protein.''; J Cell Biol, 1999 PubMed Europe PMC
  2. Burns CM, Chu H, Rueter SM, Hutchinson LK, Canton H, Sanders-Bush E, Emeson RB; ''Regulation of serotonin-2C receptor G-protein coupling by RNA editing.''; Nature, 1997 PubMed Europe PMC
  3. Brange J, Langkjoer L; ''Insulin structure and stability.''; Pharm Biotechnol, 1993 PubMed Europe PMC
  4. ''mRNA splicing - major pathway''; Reactome; R-HSA-72163.2,
  5. ''Mammalian homologue of the Caenorhabditis elegans UNC-76 protein involved in axonal outgrowth is a protein kinase C zeta-interacting protein.''; J Cell Biol, 1999
  6. Lee S, Walker CL, Karten B, Kuny SL, Tennese AA, O'Neill MA, Wevrick R; ''Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth.''; Hum Mol Genet, 2005 PubMed Europe PMC
  7. Canton H, Emeson RB, Barker EL, Backstrom JR, Lu JT, Chang MS, Sanders-Bush E; ''Identification, molecular cloning, and distribution of a short variant of the 5-hydroxytryptamine2C receptor produced by alternative splicing.''; Mol Pharmacol, 1996 PubMed Europe PMC
  8. Navarro VM, Gottsch ML, Wu M, García-Galiano D, Hobbs SJ, Bosch MA, Pinilla L, Clifton DK, Dearth A, Ronnekleiv OK, Braun RE, Palmiter RD, Tena-Sempere M, Alreja M, Steiner RA; ''Regulation of NKB pathways and their roles in the control of Kiss1 neurons in the arcuate nucleus of the male mouse.''; Endocrinology, 2011 PubMed Europe PMC
  9. Abreu AP, Macedo DB, Brito VN, Kaiser UB, Latronico AC; ''A new pathway in the control of the initiation of puberty: the MKRN3 gene.''; J Mol Endocrinol, 2015 PubMed Europe PMC
  10. Lee S, Walker CL, Karten B, Kuny SL, Tennese AA, O'Neill MA, Wevrick R; ''Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth''; Hum Mol Genet, 2005 PubMed Europe PMC
  11. Mercer RE, Michaelson SD, Chee MJ, Atallah TA, Wevrick R, Colmers WF; ''Magel2 is required for leptin-mediated depolarization of POMC neurons in the hypothalamic arcuate nucleus in mice.''; PLoS Genet, 2013 PubMed Europe PMC
  12. Maillard J, Park S, Croizier S, Vanacker C, Cook JH, Prevot V, Tauber M, Bouret SG; ''Loss of Magel2 impairs the development of hypothalamic Anorexigenic circuits.''; Hum Mol Genet, 2016 PubMed Europe PMC
  13. Colmers WF, Wevrick R; ''Leptin signaling defects in a mouse model of Prader-Willi syndrome: An orphan genetic obesity syndrome no more?''; Rare Dis, 2013 PubMed Europe PMC
  14. Homanics GE, DeLorey TM, Firestone LL, Quinlan JJ, Handforth A, Harrison NL, Krasowski MD, Rick CE, Korpi ER, Mäkelä R, Brilliant MH, Hagiwara N, Ferguson C, Snyder K, Olsen RW; ''Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior.''; Proc Natl Acad Sci U S A, 1997 PubMed Europe PMC
  15. Miller NL, Wevrick R, Mellon PL; ''Necdin, a Prader-Willi syndrome candidate gene, regulates gonadotropin-releasing hormone neurons during development.''; Hum Mol Genet, 2009 PubMed Europe PMC
  16. Delahanty RJ, Zhang Y, Bichell TJ, Shen W, Verdier K, Macdonald RL, Xu L, Boyd K, Williams J, Kang JQ; ''Beyond Epilepsy and Autism: Disruption of GABRB3 Causes Ocular Hypopigmentation.''; Cell Rep, 2016 PubMed Europe PMC
  17. Burnett LC, LeDuc CA, Sulsona CR, Paull D, et al; ''Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi Syndrome''; J Clin Invest, 2017 PubMed Europe PMC
  18. Garfield AS, Davies JR, Burke LK, Furby HV, Wilkinson LS, Heisler LK, Isles AR; ''Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT2Creceptor mediated appetite.''; Mol Brain, 2016 PubMed Europe PMC
  19. Gamell C, Gulati T, Levav-Cohen Y, Young RJ, Do H, Pilling P, Takano E, Watkins N, Fox SB, Russell P, Ginsberg D, Monahan BJ, Wright G, Dobrovic A, Haupt S, Solomon B, Haupt Y; ''Reduced abundance of the E3 ubiquitin ligase E6AP contributes to decreased expression of the INK4/ARF locus in non-small cell lung cancer.''; Sci Signal, 2017 PubMed Europe PMC
  20. Ehrhart F, Janssen KJM, Coort SL, Evelo CT, Curfs LMG2; ''Prader-Willi Syndrome and Angelman Syndrome: Visualisation of the molecular pathways for two chromosomal disorders''; World J Biol Psychiatry, 2018 PubMed Europe PMC


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106536view00:01, 6 September 2019KhanspersModified description
105788view19:47, 15 August 2019KhanspersModified description
105316view22:47, 29 July 2019AriuttaHGNC -> HGNC Accession number.
101993view19:22, 22 November 2018EgonwRemoved whitespace in PubMed identifiers and duplicate BioPax content.
101842view20:54, 12 November 2018EgonwFixed the upper case of a Uniprot identifier.
101830view09:45, 12 November 2018EgonwReplaced old Uniprot data sources with the new ones.
96172view14:29, 22 February 2018FehrhartAdded reference for pathway publication
96171view13:26, 22 February 2018FehrhartModified description
96170view13:25, 22 February 2018FehrhartModified description
95733view22:42, 18 January 2018AlexanderPicoupdated to TrEMBL
94984view13:49, 23 October 2017DeSlAdded IDs for GABA-receptor units which where missing, added linkout to GABA signalling PW.
94551view16:11, 25 September 2017EgonwReverted to version '14:42, 5 September 2017' by Egonw
94544view14:14, 22 September 2017Fehrhartcorrected some graphical issues
94543view13:09, 22 September 2017SusanQuick edit to datanode annotation or property
94376view14:42, 5 September 2017Fehrhartannotated interactions
94375view12:48, 5 September 2017Fehrhartchange of presentation of protein complex (LH, FSH)
93046view09:05, 27 July 2017FehrhartConnected interaction
92786view10:03, 6 July 2017KJanssenCorrected 1 interaction type
92755view14:21, 3 July 2017KJanssenEdited the legend and some annotations
92753view12:02, 3 July 2017FehrhartGraphical element conversion
92751view07:20, 3 July 2017FehrhartConversion graphical lines in legend
92732view11:48, 1 July 2017KJanssenCorrected a small mistake
92731view11:39, 1 July 2017KJanssenAdded a figure legend
92684view17:46, 28 June 2017MaintBotfixed unconnected
92679view16:23, 28 June 2017KJanssenMade some minor changes to the layout
92649view10:45, 27 June 2017FehrhartOntology Term : 'Angelman syndrome' added !
92648view10:44, 27 June 2017FehrhartModified description
92629view15:43, 22 June 2017KJanssenModified description
92628view15:39, 22 June 2017KJanssenModified description
92627view15:19, 22 June 2017KJanssenModified title
92611view14:15, 20 June 2017KJanssenAdded a part in the GABRB3 section
92610view12:41, 20 June 2017KJanssenFixed references, as this went wrong with the last update
92609view12:33, 20 June 2017KJanssenAdded a section for SNORD115. Also made some minor changes regarding the layout of the pathway.
92567view12:07, 16 June 2017Mkutmonfixed reference
92566view12:00, 16 June 2017KJanssenOntology Term : 'Prader-Willi syndrome' added !
92565view11:59, 16 June 2017KJanssenOntology Term : 'disease pathway' added !
92564view11:57, 16 June 2017KJanssenNew pathway

External references


View all...
NameTypeDatabase referenceComment
ARFGeneProductQ8N726 (Uniprot-TrEMBL)
ATP10AGeneProductENSG00000206190 (Ensembl)
ApoptosisPathwayWP254 (WikiPathways)
BBS4GeneProductENSG00000140463 (Ensembl)
BDNF (1-247)ProteinP23560 (Uniprot-TrEMBL)
BDNF (129-247)ProteinP23560 (Uniprot-TrEMBL)
CCND1ProteinP24385 (Uniprot-TrEMBL)
CCND2ProteinP30279 (Uniprot-TrEMBL)
CDC6GeneProductQ99741 (Uniprot-TrEMBL)
CDK4ProteinP11802 (Uniprot-TrEMBL)
CDK6ProteinQ00534 (Uniprot-TrEMBL)
CDKN2BProteinP42772 (Uniprot-TrEMBL)
CDKN2CProteinP42773 (Uniprot-TrEMBL)
CGAGeneProductP01215 (Uniprot-TrEMBL)
CYFIP1GeneProductENSG00000273749 (Ensembl)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
DLX5GeneProductENSG00000105880 (Ensembl)
E2F1GeneProductENSG00000101412 (Ensembl)
Exon IRna
FEZ1GeneProductENSG00000149557 (Ensembl)
FEZ2ProteinENSG00000171055 (Ensembl)
FSHBGeneProductP01225 (Uniprot-TrEMBL)
G1/S progressionPathwayWP45 (WikiPathways)
G2/M arrestPathway
GABA(A) receptor subunit deltaGeneProductENSG00000187730 (Ensembl)
GABA(A) receptor subunit alpha-5GeneProductP31644 (Uniprot-TrEMBL)
GABA(A) receptor subunit beta-3GeneProductP28472 (Uniprot-TrEMBL)
GABA(A) receptorPathwayWP4159 (WikiPathways)
GABRA5GeneProductENSG00000186297 (Ensembl)
GABRB3GeneProductENSG00000166206 (Ensembl)
GABRG1ProteinENSG00000163285 (Ensembl)
GABRG2ProteinENSG00000113327 (Ensembl)
GABRG3ProteinENSG00000182256 (Ensembl)
GABRR1GeneProduct2569 (Entrez Gene)
GABRR2GeneProduct2570 (Entrez Gene)
GABRR3GeneProduct200959 (Entrez Gene)
GHRH (1-108)ProteinP01286 (Uniprot-TrEMBL)
GHRH (32-75)ProteinP01286 (Uniprot-TrEMBL)
GNRH1 (24-33)ProteinP01148 (Uniprot-TrEMBL)
GNRH1 (24-92)ProteinP01148 (Uniprot-TrEMBL)
GNRH1ProteinP01148 (Uniprot-TrEMBL)
Ghrelin (1-117)ProteinQ9UBU3 (Uniprot-TrEMBL)
Ghrelin (24-51)ProteinQ9UBU3 (Uniprot-TrEMBL)
HERC2GeneProductENSG00000128731 (Ensembl)
HTR2C mRNARnaENSG00000147246 (Ensembl)
HTR2CGeneProductENSG00000147246 (Ensembl)
IPWGeneProduct6109 (HGNC Accession number)
Insulin (25-110)ProteinP01308 (Uniprot-TrEMBL)
Insulin (57-87)ProteinP01308 (Uniprot-TrEMBL)
Insulin A chain


ProteinP01308 (Uniprot-TrEMBL)
Insulin B chain


ProteinP01308 (Uniprot-TrEMBL)
Insulin processingPathwayWP2736 (WikiPathways)
KISS1ProteinQ15726 (Uniprot-TrEMBL)
L-dopaquinoneMetaboliteCHEBI:16852 (ChEBI)
L-tyrosineMetaboliteCHEBI:58315 (ChEBI)
LHBGeneProductP01229 (Uniprot-TrEMBL)
MAGEL2GeneProductENSG00000254585 (Ensembl)
MDM2GeneProductQ00987 (Uniprot-TrEMBL)
MDM4GeneProductO15151 (Uniprot-TrEMBL)
MKRN3GeneProductENSG00000179455 (Ensembl)
MSX1GeneProductENSG00000163132 (Ensembl)
Melanin biosynthesisPathwayWP3377 (WikiPathways)
NDNGeneProductENSG00000182636 (Ensembl)
NGFGeneProductENSG00000134259 (Ensembl)
NHLH2GeneProductENSG00000177551 (Ensembl)
NIPA1GeneProductENSG00000170113 (Ensembl)
NIPA2GeneProductENSG00000140157 (Ensembl)
NK3RProteinP29371 (Uniprot-TrEMBL)
NKBProteinQ2UVB8 (Uniprot-TrEMBL)
NPAP1GeneProductENSG00000185823 (Ensembl)
OCA2GeneProductENSG00000104044 (Ensembl)
Oxytocin (20-28)ProteinP01178 (Uniprot-TrEMBL)
Oxytocin-neurophysin 1 (1-125)ProteinP01178 (Uniprot-TrEMBL)
P-proteinProteinQ04671 (Uniprot-TrEMBL)
PCM1GeneProductENSG00000078674 (Ensembl)
PCSK1GeneProductENSG00000175426 (Ensembl)
POMC (1-241)ProteinP01189 (Uniprot-TrEMBL)
POMC (138-150) ProteinP01189 (Uniprot-TrEMBL)
PRKCZGeneProductENSG00000067606 (Ensembl)
PWRN1GeneProductENSG00000259905 (Ensembl)
Peptide hormone biosynthesisPathwayWP2691 (WikiPathways)


PathwayWP183 (WikiPathways)
RB1ProteinP06400 (Uniprot-TrEMBL)
SLC45A2GeneProductENSG00000164175 (Ensembl)
SNORD107GeneProductENSG00000276314 (Ensembl)
SNORD109AGeneProductENSG00000274640 (Ensembl)
SNORD109BGeneProductENSG00000239169 (Ensembl)
SNORD115@GeneProduct692218 (Entrez Gene)
  • SNORD115 primarily regulates alternate splicing of HTR2C pre-mRNA, by binding to the latter.
  • Alternate splicing and adenosine-to-inosine RNA-editing both lead to translation of less functional receptors.
  • Loss of SNORD115 might influence 5-HT2CR regulated appetite, and could therefore contribute to hyperphagia in PWS.
SNORD116@GeneProduct692236 (Entrez Gene)
SNORD64GeneProductENSG00000276610 (Ensembl)
SNRPNGeneProductENSG00000128739 (Ensembl)
SNURF-SNRPNGeneProductENSG00000128739 (Ensembl)
SNURFGeneProductENSG00000273173 (Ensembl)
Signaling pathway in GlioblastomaPathwayWP2261 (WikiPathways)
Spliceosomal A complexComplexR-HSA-72068.3 (Reactome)
Spliceosomal E complexComplexR-HSA-72057.3 (Reactome)
Synthesis, secretion

and deacylation of

PathwayWP3436 (WikiPathways)
TUBGCP5GeneProductENSG00000275835 (Ensembl)
TyrosinaseProteinP14679 (Uniprot-TrEMBL)
UBE3AGeneProductENSG00000114062 (Ensembl)
mRNA processing Major splicing pathwayPathwayWP411 (WikiPathways)
p16-INK4aProteinP42771 (Uniprot-TrEMBL)
p53ProteinP04637 (Uniprot-TrEMBL)

Annotated Interactions

No annotated interactions

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