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FLASH GENE
Symbol MECP2 contributors: mct/pgu/shn - updated : 01-02-2016
HGNC name methyl CpG binding protein 2 (Rett syndrome)
HGNC id 6990
Corresponding disease
DUPXQ28 chromosome Xq28 (MECP2) duplication
ESMR epilepsia, spasticity, mental retardation
MRX28 mental retardation, 28
MRXS31 mental retardation, syndromic 31
PPMX mental retardation with manic-depressive psychosis, pyramidal signs, and macroorchidism
RTT Rett syndrome
RTTM MECP2-related disorders in males
Location Xq28      Physical location : 153.287.263 - 153.363.188
Synonym name
  • meCp-2 protein
  • methyl-CpG-binding protein 2
  • mutant methyl CpG binding protein 2 transcript 1
  • Synonym symbol(s) AUTSX3, DKFZp686A24160, MRX16, MRX79, MRXS13, MRXSL, PPMX, RS, RTS, RTT
    DNA
    TYPE functioning gene
    STRUCTURE 75.92 kb     4 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site   enhancer   silencer
    text structure
  • escaping inactivation in any familial cases
  • four enhancer and two silencer elements that are likely to be responsible for the tissue-specific, developmental stage-specific or splice-variant-specific control of protein expression
  • binding site to the enhancer region in EGR2 intron 1 (role of MECP2 in enhancing EGR2)
  • MAPPING cloned Y linked N status confirmed
    Map cen - DXS8061 - DXS8087 - MECP2 - qter
    Physical map
    DUSP9 Xq28 dual specificity phosphatase 9 LOC347544 Xq28 similar to ribosomal protein L18a; 60S ribosomal protein L18a MGC45419 Xq28 Similar to calcium/calmodulin-dependent protein kinase 1, beta SLC6A8 Xq28 solute carrier family 6 (neurotransmitter transporter, creatine), member 8 BCAP31 Xq28 solute carrier family 6 (neurotransmitter transporter, creatine), member 8 ABCD1 Xq28 ATP-binding cassette, sub-family D (ALD), member 1 PLXNB3 Xq28 plexin B3 STK23 Xq28 serine/threonine kinase 23 IDH3G Xq28 isocitrate dehydrogenase 3 (NAD+) gamma SSR4 Xq28 signal sequence receptor, delta (translocon-associated protein delta) KIAA1444 Xq28 LU1 protein HCP45 Xq28 cytochrome c, somatic pseudogene L1CAM Xq28 L1 cell adhesion molecule (hydrocephalus, stenosis of aqueduct of Sylvius 1, MASA (mental retardation, aphasia, shuffling gait and adducted thumbs) syndrome, spastic paraplegia 1) AVPR2 Xq28 arginine vasopressin receptor 2 (nephrogenic diabetes insipidus) ARHGAP4 Xq28 Rho GTPase activating protein 4 ARD1 Xq28 ARD1 homolog, N-acetyltransferase (S. cerevisiae) RENBP Xq28 renin binding protein HCFC1 Xq28 host cell factor C1 (VP16-accessory protein) CXorf12 Xq28 chromosome X open reading frame 12 IRAK1 Xq28 interleukin-1 receptor-associated kinase 1 MECP2 Xq28 methyl CpG binding protein 2 (Rett syndrome) OPN1LW Xq28 opsin 1 (cone pigments), long-wave-sensitive (color blindness, protan) OPN1MW Xq28 opsin 1 (cone pigments), medium-wave-sensitive (color blindness, deutan) CXorf2 Xq28 chromosome X open reading frame 2 TKTL1 Xq28 transketolase-like 1 FLNA Xq28 filamin A, alpha (actin binding protein 280)
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    4 splicing 10241 53 486 highly expressed in the brain 2006 16932552
  • also called MECP2A
  • giant 3'utr
  • see also PMID: 16708070
  • 3 splicing polyA site 1734 75 498 prevalent in brain, thymus, lung 2006 16932552
  • also called MECP2B
  • lacking the 124 -nucleotides exon 2
  • an alternative N-terminus transcribed fromm exon 1
  • localized in the nucleus
  • not commonly mutated in X-linked mental retardation (PMID: 16932552)
  • EXPRESSION
    Rna function Mecp2 mRNA transcripts are highly expressed in lung, skeletal muscle and heart, moderate in brain and low in liver and spleen
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticspleen   highly
    Cardiovascularheart   lowly
    Nervousbrain   highly Homo sapiens
    Respiratorylung   highly
    Urinarykidney   lowly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Nervouscentral    Homo sapiens
    Nervousperipherous   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Lymphoid/Immunelymphocyte
    Nervousneuron Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo, fetal, neonatal, growth/childhood
    Text cortex
    PROTEIN
    PHYSICAL PROPERTIES basic
    STRUCTURE
    motifs/domains
  • N-terminal methylated DNA-binding domain
  • a methyl-CpG-binding (MBD) and a central transcription regulation domain
  • a nuclear localization signal (NLS) reported to reside between amino acids 255-271
  • a transcriptional repression (TRD) domains, repressing the MAGEA1, MAGEA2, MAGEA3, MAGEA12 promoters and corepressor interacting region
  • three AT-hook-like domains over a stretch of 250 AAs, like HMGA DNA-bending proteins, and the AT-Hook 2 domain is important for chromatin maintenance and ATRX localization
  • (r)GPR(k) motifs and SPKK motifs that have been found to bind to minor groove of at-rich DNA
  • C terminal segment with WW domain binding region
  • of unknown function
    HOMOLOGY
    interspecies ortholog to Mecp2, Mus musculus
    ortholog to Mecp2, Rattus norvegicus
    ortholog to MECP2, Pan troglodytes
    ortholog to mecp2, Danio rerio
    Homologene
    FAMILY
    CATEGORY regulatory , DNA associated , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome,heterochromosome
    basic FUNCTION
  • involved in the regulation of gene expression (in normal neuronal maturation)
  • selectivity binds 5'methyl cytosine residues in symmetrically positioned CpG dinucleotides, preferentially in the promoter regions of genes subject to transcriptional silencing after DNA methylation
  • transcriptional repression either dependent on chromatin modification by histone deacetylation, or chromatin independent, not affecting imprinted gene expression in blood and brain
  • may regulate the transcription of activity dependent genes in neuronal cells, which is important in synapse development and neuronal plasticity
  • multifunctional corepressor of methylated genes, recruited on repressed promoters and associated with component of the SWI/SNF complex
  • assembling novel secondary chromatin structures independent of DNA modification, may be silencing chromatin and involved in its organization
  • multifunctional protein, playing a role as transcriptional repressor and also splicing regulator
  • regulating UBE3A and GABRB3 in postnatal brain
  • regulating splicing of reporter minigenes
  • unlikely to be the CpG binding molecule that translates a methylation signal in imprinting
  • natural inhibitor of the basic helix-loop-helix transcription factors and the retinoblastoma tumor suppressor protein
  • modulating HP1 heterochromatin association during myogenic differentiation
  • regulates the expression of a wide range of genes in the hypothalamus and that it can function as both an activator and a repressor of transcription
  • silencing OF MECP2 and MBD1 appear to affect cellular processes independently and discrete sets of genes involved in cellular proliferation, apoptosis, invasion and migration are targeted by each protein
  • MBD2 and MECP2 regulate distinct transitional stages of olfactory receptor neuron (ORN) differentiation
  • plays a critical role in interpreting epigenetic signatures that command chromatin conformation and regulation of gene transcription
  • can epigenetically regulate specific miRNAs in adult neural stem cells
  • roles in the development and function of the mesolimbocortical dopamine circuit
  • capable of influencing expression of genes associated with the D4Z4 repeat on chromosome 4
  • binds cooperatively to its substrate and competes with histone H1 for chromatin binding sites
  • is not essential for early wiring of the nervous system but instead may only be required at late stages
  • critical for normal function of GABA-releasing neurons and subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes
  • act as a DNA methylation-dependent transcriptional repressor, but may have additional roles in regulating gene expression and chromatin structure
  • binds preferentially to methylated CpGs and regulates gene expression by causing changes in chromatin structure
  • likely enhanced role for MECP2 in the aging brain
  • MECP2 shares likely a common ancestry with the HMGA family of proteins
  • removal of MECP2 from gene promoters activates transcription
  • clearly performs important functions besides classical transcriptional repression
  • potentially involved in cholesterol homeostasis
  • MECP2 serves as a critical safeguard that confers Tregs with resilience against inflammation
  • is a nuclear protein with important roles in regulating chromatin structure and gene expression
  • CELLULAR PROCESS nucleotide, transcription, regulation
    nucleotide, RNA splicing
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • complexing with HDAC1, HDAC2
  • complexing with biochemically defined nucleosomal arrays
  • INTERACTION
    DNA
  • IkappaBalpha promoter via a methyl-CpG-dependent mechanism
  • RNA
    small molecule cofactor,
  • methylated CpG dinucleotides
  • protein
  • mSin3, c-Ski and N-CoR
  • HMGB1
  • DNA (cytosine-5-)-methyltransferase 1, DNMT1
  • PU.1
  • Xenopus laevis protein of 20 kDa, p20
  • Brahma, Brm
  • cyclin-dependent kinase-like 5, CDKL5
  • alpha thalassemia/mental retardation syndrome X-linked, ATRX
  • target of DLX5
  • HP1
  • inner nuclear membrane lamin B receptor LBR
  • SMARCA2 and SLC6A2
  • YY1
  • MECP2 and MBD2 direct interactions could crosslink chromatin fibers and therefore give novel insight into the molecular mechanism of MBD mediated global heterochromatin architecture
  • HTT-MECP2 interactions are enhanced in the presence of the expanded polyglutamine (polyQ) tract and are stronger in the nucleus compared with the cytoplasm
  • is critical to sustain FOXP3 expression in Tregs during inflammation
  • RNF4 does not promote DNA demethylation, but mediates the ubiquitination of MECP2, a methyl-CpG-binding domain (MBD) protein
  • PSIP1 is an autoantigen in prostate cancer that closely interacts with another 70kD dense fine speckled (DFS) nuclear protein, MECP2
  • KPNA3 and KPNA4 are key binding partners of MECP2, and mediate the nuclear import of MECP2
  • memory associated WWC1 is a target of MECP2 in regulating dendritic growth
  • cell & other
    REGULATION
    Phosphorylated by homeodomain-interacting protein kinase 2 , HIPK2
    Other target of DLX5 (dysregulation of DLX5 and LOI in mutations of Rett syndrome)
    precise control of MECP2 is critical for normal behavior and neurodevelopmental disorders will result from a subtle reduction in the expression
    phosphorylation of MECP2 modulates its dynamic function in neurons transiting between resting and active states within neural circuits that underlie behaviors
    MECP2 contains multiple posttranslational modifications, including phosphorylation, acetylation, and ubiquitylation
    ASSOCIATED DISORDERS
    corresponding disease(s) RTT , RTTM , MRX28 , PPMX , MRXS31 , ESMR , DUPXQ28
    related resource RettBASE
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation      
    in sporadic RTT, mutation exclusively of paternal origin
    constitutional somatic mutation      
    somatic mosaicism in male (with classic RTT syndrome)
    constitutional   amplification    
    duplication in mental retardation in males
    constitutional germinal mutation      
    in autism sporadic, rare cases
    tumoral     --over  
    in cancer prostate cells
    constitutional     --other loss of function
    a 50p100 decrease in MECP2 levels might indeed cause disease, and misregulation may be a common feature of many neurodevelopmental disorders
    constitutional       loss of function
    neural cell fate and neuronal maintenance may be perturbed by senescence triggered by impaired MECP2 activity either before or after neural differentiation (
    Susceptibility
  • to sporadic autism
  • to reduced cortical surface area
  • Variant & Polymorphism other common MECP2 haplotype associates with reduced cortical surface area
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    mental retardationother 
    a lower dosage of gentamicin was enough to increase full-length MECP2 levels in RTT neurons, rescuing glutamatergic synapses
    mental retardationother 
    various steps in the cholesterol pathway may be valid targets for treatment of Rett sdr
    ANIMAL & CELL MODELS
  • overexpression of MeCP2 in the mouse heart causes embryonic lethality with cardiac septum hypertrophy and dysregulated expression of MeCP2 in skeletal tissue produces severe malformations
  • mice bearing a hypomorphic mutation in Mecp2 display altered behavioral responses to acute and repeated AMPH treatment and changes in both the development and plasticity of striatal synapses
  • in globally MeCP2-deficient mice, re-expression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern, and greatly prolonged lifespan compared to globally null mice
  • neuron-specific deletion of MeCP2 recapitulates the RTT symptoms of the whole-body KO mouse, implicating an essential role for MeCP2 in neurons
  • decreased dopamine transmission due to heterogeneous Mecp2 expression contributes to the parkinsonian features of RTT in Mecp2(+/-) mice
  • mutations occurring in Rett patients are defective in the chromatin architecture function of MeCP2
  • cholesterol homeostasis is disrupted in Mecp2 mutant mice
  • loss of MECP2 causes mislocalization of the ATRX in the hippocampus and cortex of symptomatic KO mice