MECP2 and associated Rett syndrome (WP3584)

MECP2 (methyl-CpG binding protein 2) is in many mammals an important regulator of neuronal function and development. It affects all cell types, especially neurons but also astrocytes, oligodendrocytes, and glial cells. MECP2 plays an important role in neuronal differentiation, maturation, morphology and function and influences synaptic plasticity. Mutations impairing the proper function of MECP2 are mainly associated with the Rett syndrome but may also contribute to other neurological disorders like schizophrenia, FASD (fetal alcohol syndrome), PPM-X-syndrome, autism, Prader-Will-syndrome, and Angelman-syndrome. Dependant on the cofactors MECP2 acts as an activator or repressor of transcription and micro RNA production. It affects RNA splicing and regulates chromatin structure together with HP1 and interferes in methylation of DNA (epigenetics). The expression of MECP2 itself is highly regulated by promotor elements, cis-regulatory elements, polyadenylation, promotor DNA methylation and miRNA. Please cite this pathways as: Ehrhart et al. 2016 - the pathway version in the paper is 90609. Proteins on this pathway have targeted assays available via the [ CPTAC Assay Portal]
last edited


Fehrhart, Egonw, Khanspers, Ryanmiller, Mkutmon, AlexanderPico, MaintBot, L Dupuis, and Eweitz

Cited In


Homo sapiens


Diseases Rare Diseases


Disease Ontology: Rett syndrome

Pathway Ontology: disease pathway


Label Type Compact Identifier
Dopamine Metabolite hmdb:HMDB0000073
NCOR1 GeneProduct ensembl:ENSG00000141027
hsa-miR-222-3p Rna mirbase.mature:MIMAT0000279
MYT1 GeneProduct ensembl:ENSG00000196132
BRN3 GeneProduct ensembl:ENSG00000152192
hsa-miR-184 Rna mirbase.mature:MIMAT0000454
hsa-miR-29b-1-5p Rna mirbase.mature:MIMAT0004514
hsa-miR-193a-5p Rna mirbase.mature:MIMAT0004614
DLX5 GeneProduct ensembl:ENSG00000105880
MTOR GeneProduct ensembl:ENSG00000198793
APOC2 GeneProduct ensembl:ENSG00000234906
GABA Metabolite chebi:16865
hsa-miR-137 Rna mirbase.mature:MIMAT0000429
hsa-miR-329-5p Rna mirbase.mature:MIMAT0026555
HDAC1 GeneProduct ensembl:ENSG00000116478
BDNF GeneProduct ensembl:ENSG00000176697
SST GeneProduct ensembl:ENSG00000157005
HB1 GeneProduct None
NREP GeneProduct ensembl:ENSG00000134986
TET3 GeneProduct ensembl:ENSG00000187605
PI3K/MAPK Pathway wikipathways:WP382
hsa-miR-199a-5p Rna mirbase.mature:MIMAT0000231
Glycine Metabolite hmdb:HMDB0000123
MECP2 GeneProduct ensembl:ENSG00000169057
BRN2 GeneProduct ensembl:ENSG00000184486
DLX6 GeneProduct ensembl:ENSG00000006377
hsa-miR-130a Rna mirbase.mature:MIMAT0000425
HP1 GeneProduct None
SMC3 GeneProduct ensembl:ENSG00000108055
hsa-miR-199a-3p Rna mirbase.mature:MIMAT0000232
hsa-miR-130b-3p Rna mirbase.mature:MIMAT0000691
hsa-miR-146b-3p Rna miRBase mature sequence
Norepinephrine Metabolite HMDB
hsa-miR-483-5p Rna miRBase mature sequence
MEF2C GeneProduct Ensembl
TAP1 GeneProduct Ensembl
Norepinephrine Metabolite HMDB
UBE3A GeneProduct Ensembl
NMDA Metabolite HMDB
RBFOX1 GeneProduct Ensembl
CNP GeneProduct Ensembl
Glutamate Metabolite chebi:29987
TET2 GeneProduct ensembl:ENSG00000168769
SGK1 GeneProduct ensembl:ENSG00000118515
Serotonin Metabolite hmdb:HMDB0000259
FKBP5 GeneProduct ensembl:ENSG00000096060
RPS6 GeneProduct ensembl:ENSG00000137154
hsa-miR-132-5p Rna mirbase.mature:MIMAT0004594
Ak087060 GeneProduct None
EZH2 GeneProduct ensembl:ENSG00000106462
GAMT GeneProduct ensembl:ENSG00000130005
hsa-miR-197-3p Rna mirbase.mature:MIMAT0000227
hsa-miR-199b-5p Rna mirbase.mature:MIMAT0000263
AKT1 GeneProduct ensembl:ENSG00000142208
H3 GeneProduct None
MPP1 GeneProduct ensembl:ENSG00000130830
OPRK1 GeneProduct ensembl:ENSG00000082556
Trofinetide Metabolite pubchem.compound:11318905
hsa-miR-296-5p Rna mirbase.mature:MIMAT0000690
ARHGEF26 GeneProduct ensembl:ENSG00000114790
SIN3A GeneProduct ensembl:ENSG00000169375
IGF2 GeneProduct ensembl:ENSG00000167244
Ak081227 GeneProduct None
Dopamine Metabolite hmdb:HMDB0000073
SP1 GeneProduct ensembl:ENSG00000185591
GAD1 GeneProduct ensembl:ENSG00000128683
TAF1 GeneProduct ensembl:ENSG00000147133
HNRNPH1 GeneProduct ensembl:ENSG00000169045
hsa-miR-342-3p Rna mirbase.mature:MIMAT0000753
CSRP1 GeneProduct ensembl:ENSG00000159176
hsa-miR-382-3p Rna mirbase.mature:MIMAT0022697
hsa-miR-221-5p Rna mirbase.mature:MIMAT0004568
hsa-miR-30a-3p Rna mirbase.mature:MIMAT0000088
GRID1 GeneProduct ensembl:ENSG00000182771
hsa-miR-409-3p Rna mirbase.mature:MIMAT0001639
CDON GeneProduct ensembl:ENSG00000064309
MYT1 GeneProduct ensembl:ENSG00000196132
C/EBP GeneProduct ensembl:ENSG00000221869
hsa-miR-146a-5p Rna mirbase.mature:MIMAT0000449
CAMK2A GeneProduct ensembl:ENSG00000070808
MBP GeneProduct ensembl:ENSG00000197971
hsa-miR-221-3p Rna mirbase.mature:MIMAT0000278
Melatonin Metabolite hmdb:HMDB0001389
BCL6 GeneProduct ensembl:ENSG00000113916
GABRR2 GeneProduct ensembl:ENSG00000111886
CTCF GeneProduct ensembl:ENSG00000102974
SP3 GeneProduct ensembl:ENSG00000172845
hsa-miR-187-5p Rna mirbase.mature:MIMAT0004561
hsa-miR-152-3p Rna mirbase.mature:MIMAT0000438
PRPF3 GeneProduct ensembl:ENSG00000134748
E2F1 GeneProduct ensembl:ENSG00000101412
AMPA GeneProduct ensembl:ENSG00000155511
REST GeneProduct ensembl:ENSG00000084093
MAG GeneProduct ensembl:ENSG00000105695
GPRIN1 GeneProduct ensembl:ENSG00000169258
Serotonin Metabolite hmdb:HMDB0000259
TET1 GeneProduct ensembl:ENSG00000138336
IGF1R GeneProduct ensembl:ENSG00000140443
hsa-miR-92a-3p Rna mirbase.mature:MIMAT0000092
HNRNPF GeneProduct ensembl:ENSG00000169813
hsa-miR-122-5p Rna mirbase.mature:MIMAT0000421
Myoinositol Metabolite hmdb:HMDB0000211
Cytosine methylation Pathway wikipathways:WP3585
YB1 GeneProduct ensembl:ENSG00000065978
MECP2 GeneProduct ensembl:ENSG00000169057
MECP2 GeneProduct ensembl:ENSG00000169057
SP1 GeneProduct ensembl:ENSG00000185591
Glutamate Metabolite chebi:29987
GABA Metabolite chebi:16865
CREB1 GeneProduct ensembl:ENSG00000118260
RPS6 GeneProduct ensembl:ENSG00000137154
BDNF GeneProduct ensembl:ENSG00000176697
GAMT GeneProduct ensembl:ENSG00000130005
Glutamate Metabolite chebi:29987
GABA Metabolite chebi:16865
MECP2 GeneProduct ensembl:ENSG00000169057
D-serine Metabolite chebi:16523
IGF1 GeneProduct ensembl:ENSG00000017427
FOXG1 GeneProduct ensembl:ENSG00000176165
PI3K GeneProduct None
PTEN GeneProduct ensembl:ENSG00000171862
DHX9 GeneProduct ensembl:ENSG00000135829
FUS GeneProduct ensembl:ENSG00000089280
HNRNPF GeneProduct ensembl:ENSG00000169813
TARDBP GeneProduct ensembl:ENSG00000120948
PSIP1 GeneProduct ensembl:ENSG00000164985
FUT8 GeneProduct ensembl:ENSG00000033170
FGF2 GeneProduct ensembl:ENSG00000138685
GRIN1 GeneProduct ensembl:ENSG00000176884
FGF3 GeneProduct ensembl:ENSG00000186895
FGF4 GeneProduct ensembl:ENSG00000075388
FGF5 GeneProduct ensembl:ENSG00000138675
NF1 GeneProduct ensembl:ENSG00000196712
DLX5 GeneProduct ensembl:ENSG00000105880
GRIA1 GeneProduct ensembl:ENSG00000155511
GRIA3 GeneProduct ensembl:ENSG00000125675
GRIA4 GeneProduct ensembl:ENSG00000152578


  1. Peruzzi F, Prisco M, Dews M, Salomoni P, Grassilli E, Romano G, et al. Multiple signaling pathways of the insulin-like growth factor 1 receptor in protection from apoptosis. Mol Cell Biol. 1999 Oct;19(10):7203–15. PubMed Europe PMC Scholia
  2. Young JI, Hong EP, Castle JC, Crespo-Barreto J, Bowman AB, Rose MF, et al. Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17551–8. PubMed Europe PMC Scholia
  3. Liu J, Francke U. Identification of cis-regulatory elements for MECP2 expression. Hum Mol Genet. 2006 Jun 1;15(11):1769–82. PubMed Europe PMC Scholia
  4. Burmistrova OA, Goltsov AY, Abramova LI, Kaleda VG, Orlova VA, Rogaev EI. MicroRNA in schizophrenia: genetic and expression analysis of miR-130b (22q11). Biochemistry (Mosc). 2007 May;72(5):578–82. PubMed Europe PMC Scholia
  5. Nomura T, Kimura M, Horii T, Morita S, Soejima H, Kudo S, et al. MeCP2-dependent repression of an imprinted miR-184 released by depolarization. Hum Mol Genet. 2008 Apr 15;17(8):1192–9. PubMed Europe PMC Scholia
  6. Chahrour M, Jung SY, Shaw C, Zhou X, Wong STC, Qin J, et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science. 2008 May 30;320(5880):1224–9. PubMed Europe PMC Scholia
  7. Singh J, Saxena A, Christodoulou J, Ravine D. MECP2 genomic structure and function: insights from ENCODE. Nucleic Acids Res. 2008 Nov;36(19):6035–47. PubMed Europe PMC Scholia
  8. Bickerdike MJ, Thomas GB, Batchelor DC, Sirimanne ES, Leong W, Lin H, et al. NNZ-2566: a Gly-Pro-Glu analogue with neuroprotective efficacy in a rat model of acute focal stroke. J Neurol Sci. 2009 Mar 15;278(1–2):85–90. PubMed Europe PMC Scholia
  9. Lusardi TA, Farr CD, Faulkner CL, Pignataro G, Yang T, Lan J, et al. Ischemic preconditioning regulates expression of microRNAs and a predicted target, MeCP2, in mouse cortex. J Cereb Blood Flow Metab. 2010 Apr;30(4):744–56. PubMed Europe PMC Scholia
  10. Szulwach KE, Li X, Smrt RD, Li Y, Luo Y, Lin L, et al. Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J Cell Biol. 2010 Apr 5;189(1):127–41. PubMed Europe PMC Scholia
  11. Maezawa I, Jin L-W. Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate. J Neurosci. 2010 Apr 14;30(15):5346–56. PubMed Europe PMC Scholia
  12. Newnham CM, Hall-Pogar T, Liang S, Wu J, Tian B, Hu J, et al. Alternative polyadenylation of MeCP2: Influence of cis-acting elements and trans-acting factors. RNA Biol. 2010;7(3):361–72. PubMed Europe PMC Scholia
  13. Liu C, Teng Z-Q, Santistevan NJ, Szulwach KE, Guo W, Jin P, et al. Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Cell Stem Cell. 2010 May 7;6(5):433–44. PubMed Europe PMC Scholia
  14. Vora P, Mina R, Namaka M, Frost EE. A novel transcriptional regulator of myelin gene expression: implications for neurodevelopmental disorders. Neuroreport. 2010 Oct 6;21(14):917–21. PubMed Europe PMC Scholia
  15. Urdinguio RG, Fernandez AF, Lopez-Nieva P, Rossi S, Huertas D, Kulis M, et al. Disrupted microRNA expression caused by Mecp2 loss in a mouse model of Rett syndrome. Epigenetics. 2010 Oct 1;5(7):656–63. PubMed Europe PMC Scholia
  16. Long SW, Ooi JYY, Yau PM, Jones PL. A brain-derived MeCP2 complex supports a role for MeCP2 in RNA processing. Biosci Rep. 2011 Oct;31(5):333–43. PubMed Europe PMC Scholia
  17. Ricciardi S, Boggio EM, Grosso S, Lonetti G, Forlani G, Stefanelli G, et al. Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum Mol Genet. 2011 Mar 15;20(6):1182–96. PubMed Europe PMC Scholia
  18. Smith RM, Sadee W. Synaptic signaling and aberrant RNA splicing in autism spectrum disorders. Front Synaptic Neurosci. 2011 Jan 26;3:1. PubMed Europe PMC Scholia
  19. Guo Y, Chen Y, Carreon S, Qiang M. Chronic intermittent ethanol exposure and its removal induce a different miRNA expression pattern in primary cortical neuronal cultures. Alcohol Clin Exp Res. 2012 Jun;36(6):1058–66. PubMed Europe PMC Scholia
  20. Wu W, Gu W, Xu X, Shang S, Zhao Z. Downregulation of CNPase in a MeCP2 deficient mouse model of Rett syndrome. Neurol Res. 2012 Mar;34(2):107–13. PubMed Europe PMC Scholia
  21. Gonzales ML, Adams S, Dunaway KW, LaSalle JM. Phosphorylation of distinct sites in MeCP2 modifies cofactor associations and the dynamics of transcriptional regulation. Mol Cell Biol. 2012 Jul;32(14):2894–903. PubMed Europe PMC Scholia
  22. Yasui DH, Xu H, Dunaway KW, Lasalle JM, Jin L-W, Maezawa I. MeCP2 modulates gene expression pathways in astrocytes. Mol Autism. 2013 Jan 25;4(1):3. PubMed Europe PMC Scholia
  23. Han K, Gennarino VA, Lee Y, Pang K, Hashimoto-Torii K, Choufani S, et al. Human-specific regulation of MeCP2 levels in fetal brains by microRNA miR-483-5p. Genes Dev. 2013 Mar 1;27(5):485–90. PubMed Europe PMC Scholia
  24. Petazzi P, Sandoval J, Szczesna K, Jorge OC, Roa L, Sayols S, et al. Dysregulation of the long non-coding RNA transcriptome in a Rett syndrome mouse model. RNA Biol. 2013 Jul;10(7):1197–203. PubMed Europe PMC Scholia
  25. Lyst MJ, Ekiert R, Ebert DH, Merusi C, Nowak J, Selfridge J, et al. Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nat Neurosci. 2013 Jul;16(7):898–902. PubMed Europe PMC Scholia
  26. Volkmann I, Kumarswamy R, Pfaff N, Fiedler J, Dangwal S, Holzmann A, et al. MicroRNA-mediated epigenetic silencing of sirtuin1 contributes to impaired angiogenic responses. Circ Res. 2013 Sep 27;113(8):997–1003. PubMed Europe PMC Scholia
  27. Cartron P-F, Nadaradjane A, Lepape F, Lalier L, Gardie B, Vallette FM. Identification of TET1 Partners That Control Its DNA-Demethylating Function. Genes Cancer. 2013 May;4(5–6):235–41. PubMed Europe PMC Scholia
  28. Liyanage VRB, Rastegar M. Rett syndrome and MeCP2. Neuromolecular Med. 2014 Jun;16(2):231–64. PubMed Europe PMC Scholia
  29. Chen J, Alberts I, Li X. Dysregulation of the IGF-I/PI3K/AKT/mTOR signaling pathway in autism spectrum disorders. Int J Dev Neurosci. 2014 Jun;35:35–41. PubMed Europe PMC Scholia
  30. Livide G, Patriarchi T, Amenduni M, Amabile S, Yasui D, Calcagno E, et al. GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells. Eur J Hum Genet. 2015 Feb;23(2):195–201. PubMed Europe PMC Scholia
  31. Mitchell AC, Jiang Y, Peter C, Akbarian S. Transcriptional regulation of GAD1 GABA synthesis gene in the prefrontal cortex of subjects with schizophrenia. Schizophr Res. 2015 Sep;167(1–3):28–34. PubMed Europe PMC Scholia
  32. Li R, Dong Q, Yuan X, Zeng X, Gao Y, Chiao C, et al. Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome. PLoS Genet. 2016 Jun 28;12(6):e1006129. PubMed Europe PMC Scholia
  33. Oosterholt SP, Horrigan J, Jones N, Glass L, Della Pasqua O. Population pharmacokinetics of NNZ-2566 in healthy subjects. Eur J Pharm Sci. 2017 Nov 15;109S:S98–107. PubMed Europe PMC Scholia