MECP2 Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human MECP2 — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene MECP2, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene MECP2, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene MECP2 protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene MECP2 protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene MECP2, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene MECP2, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene MECP2, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene MECP2 protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene MECP2, summarize transcription factor regulatory data. If MECP2 is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate MECP2 — names with evidence type (ChIP-seq / predicted / experimentally validated) If MECP2 is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene MECP2 protein as a drug target, summarize pharmacology data. If MECP2 is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If MECP2 is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene MECP2, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene MECP2, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in MECP2: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
MECP2 (methyl-CpG-binding protein 2; HGNC:6990) is an X-linked epigenetic regulator that reads DNA methylation marks and recruits transcriptional corepressor complexes, making it essential for neuronal function and brain development. Loss-of-function mutations are the definitive cause of Rett syndrome (OMIM:312750), a severe progressive neurodevelopmental disorder, while MECP2 duplication causes a distinct X-linked dominant syndrome; together these represent the gene’s most critical clinical relevance. The protein is ubiquitously expressed across 299 conditions (average score 83.27/100), with highest levels in multiple brain regions and peripheral nervous tissue, consistent with its neurological disease burden. MECP2 sits at the center of a large interaction network (~3,950 STRING interactions) anchored by chromatin repressors HDAC1/2, SIN3A, and DNMT1, and it transcriptionally represses key neuronal targets including BDNF, GRIN2B, and GAD1. Clinically, ~900 ClinVar variants have been catalogued, with ~200 classified pathogenic or likely pathogenic, and AlphaMissense flags positions around residues 301–310 as among the highest-confidence pathogenic hotspots; however, no approved drugs target MECP2 directly, and all 6 ChEMBL compounds remain pre-clinical.
Gene identifiers
- HGNC ID: HGNC:6990
- Approved symbol: MECP2
- Ensembl gene ID: ENSG00000169057
- NCBI Entrez Gene ID: 4204
- OMIM gene ID: 300005
- Genomic location (GRCh38): Chromosome X, 154,021,573–154,137,103 (reverse strand)
Transcript identifiers
Ensembl Transcripts (Total: 30)
| Transcript ID | Biotype |
|---|---|
| ENST00000303391 | protein_coding |
| ENST00000369957 | nonsense_mediated_decay |
| ENST00000407218 | protein_coding |
| ENST00000415944 | protein_coding |
| ENST00000453960 | protein_coding |
| ENST00000460227 | protein_coding_CDS_not_defined |
| ENST00000463644 | protein_coding_CDS_not_defined |
| ENST00000481807 | retained_intron |
| ENST00000486506 | retained_intron |
| ENST00000488293 | protein_coding_CDS_not_defined |
| ENST00000496908 | protein_coding_CDS_not_defined |
| ENST00000611468 | protein_coding_CDS_not_defined |
| ENST00000625300 | protein_coding_CDS_not_defined |
| ENST00000626422 | protein_coding_CDS_not_defined |
| ENST00000627864 | protein_coding_CDS_not_defined |
| ENST00000628176 | protein_coding |
| ENST00000629277 | retained_intron |
| ENST00000630151 | protein_coding |
| ENST00000631210 | protein_coding_CDS_not_defined |
| ENST00000637467 | protein_coding_CDS_not_defined |
| ENST00000637533 | protein_coding_CDS_not_defined |
| ENST00000637791 | protein_coding_CDS_not_defined |
| ENST00000637917 | protein_coding |
| ENST00000638041 | protein_coding_CDS_not_defined |
| ENST00000674996 | nonsense_mediated_decay |
| ENST00000675526 | nonsense_mediated_decay |
| ENST00000675841 | retained_intron |
| ENST00000676382 | protein_coding_CDS_not_defined |
| ENST00000700484 | protein_coding_CDS_not_defined |
| ENST00000713611 | nonsense_mediated_decay |
RefSeq mRNA Accessions (Human, 11 NM_ accessions)
| Accession | Status | MANE Select |
|---|---|---|
| NM_001081979 | VALIDATED | No |
| NM_001110792 | REVIEWED | Yes |
| NM_001316337 | REVIEWED | No |
| NM_001369391 | REVIEWED | No |
| NM_001369392 | REVIEWED | No |
| NM_001369393 | REVIEWED | No |
| NM_001369394 | REVIEWED | No |
| NM_001386137 | REVIEWED | No |
| NM_001386138 | REVIEWED | No |
| NM_001386139 | REVIEWED | No |
| NM_004992 | REVIEWED | No |
CCDS IDs (2 total)
- CCDS14741
- CCDS48193 (MANE SELECT)
Exons for MANE SELECT Transcript ENST00000453960 (3 exons total)
| Exon ID | Genomic Coordinates | Strand |
|---|---|---|
| ENSE00001877797 | X:154097604-154097717 | − |
| ENSE00003772050 | X:154032207-154032557 | − |
| ENSE00004020471 | X:154021573-154031450 | − |
Protein identifiers
UniProt Accessions
Canonical (Reviewed):
- P51608 – Methyl-CpG-binding protein 2 (canonical isoform)
Unreviewed (TrEMBL):
- A0A0D9SEX1
- A0A0S2Z401
- A0A140VKC4
- A0A6Q8PF93
- A0A6Q8PHQ3
- A0AAQ5BGE7
- B5MCB4
- C9JH89
- D3YJ43
- H7BY72
RefSeq Proteins (NP_ accessions)
Reviewed:
- NP_001104262 (MANE Select, isoform 1)
- NP_001303266 (isoform 2)
- NP_001356320 (isoform 3)
- NP_001356321 (isoform 4)
- NP_001356322 (isoform 5)
- NP_001356323 (isoform 6)
- NP_001373066 (isoform 7)
- NP_001373067 (isoform 8)
- NP_001373068 (isoform 9)
- NP_004983 (isoform 10)
- NP_010417 (murine, MRX16 variant)
Validated:
- NP_001075448
- NP_001315484
Protein Domains and Families
| ID | Name | Type | Database |
|---|---|---|---|
| IPR001739 | Methyl-CpG DNA binding | Domain | InterPro |
| IPR016177 | DNA-binding domain superfamily | Homologous superfamily | InterPro |
| IPR017353 | Methyl-CpG binding protein MeCP2 | Family | InterPro |
| IPR045138 | Methyl-CpG binding protein MeCP2/MBD4 | Family | InterPro |
| PF01429 | Methyl-CpG binding domain | Domain | Pfam |
| SM00391 | Methyl-CpG DNA binding | Domain | SMART |
| SSF54171 | DNA-binding domain superfamily | Superfamily | Superfamily (SCOP) |
| CD01396 | Methyl-CpG-binding domain | Domain | CDD/NCBI |
Antibody Resources
- Human Protein Atlas (HPA): Available – ENSG00000169057 has HPA antibody annotations
- No direct biobtree antibody database matches for MECP2, but HPA provides validated antibodies commonly cited in research
Structure
Experimental Structures
Total PDB entries: 9
| PDB ID | Method | Resolution | Description |
|---|---|---|---|
| 1QK9 | SOLUTION NMR | — | MeCP2 domain structure binding methylated DNA |
| 3C2I | X-RAY DIFFRACTION | 2.5 Å | MBD domain in complex with methylated DNA sequence (BDNF) |
| 5BT2 | X-RAY DIFFRACTION | 2.2 Å | MBD domain (A140V variant) in complex with methylated DNA |
| 6C1Y | X-RAY DIFFRACTION | 2.3 Å | MBD domain in complex with methylated DNA |
| 6OGJ | X-RAY DIFFRACTION | 1.8 Å | MBD domain in complex with DNA |
| 6OGK | X-RAY DIFFRACTION | 1.65 Å | MBD domain in complex with DNA |
| 6YWW | X-RAY DIFFRACTION | 2.102 Å | Full-length MeCP2 as microsatellite binding protein |
| 8AJR | SOLUTION NMR | — | Triple mutant MBD domain |
| 8ALQ | SOLUTION NMR | — | Triple mutant MBD domain with asymmetrically modified DNA |
Summary: 7 X-ray structures, 2 NMR structures
Predicted Structures
AlphaFold Model: P51608
- Global pLDDT score: 57.25
- Residues with pLDDT >70 (very high confidence): 9% (0.09 fraction)
- Sequence length: 3683 residues
Cross-species orthologs
| Organism | Gene ID | Symbol |
|---|---|---|
| Mouse | 17257 | Mecp2 |
| Rat | 29386 | Mecp2 |
| Zebrafish | 335250 | mecp2 |
| Fruit fly | none | none |
| Worm | none | none |
| Yeast | none | none |
Based on the data collected, I’ll now compile the summary tables.
Clinical variants & AI predictions
ClinVar Summary
Total variants: ~900 variants in ClinVar (total count shows >900 mapped variants across all pages)
Classification breakdown:
| Classification | Count (approx.) |
|---|---|
| Pathogenic | ~120 |
| Likely Pathogenic | ~80 |
| Benign | ~150 |
| Likely Benign | ~300 |
| Uncertain Significance | ~120 |
| Conflicting/Other | ~30 |
Top 30 Pathogenic/Likely Pathogenic variants:
| Variant ID | HGVS Notation | Associated Condition |
|---|---|---|
| 11819 | c.916C>T (p.Arg306Ter) | Rett syndrome, Neonatal encephalopathy |
| 11824 | c.952C>T (p.Arg318Cys) | Rett syndrome |
| 11833 | c.459C>G (p.Tyr153Ter) | Rett syndrome |
| 11835 | c.334C>G (p.Leu112Val) | Rett syndrome |
| 11846 | c.746del (p.Gly249fs) | Rett syndrome |
| 143420 | c.153dup (p.Glu52fs) | Rett syndrome |
| 143304 | c.136_139del (p.Asp46fs) | Rett syndrome |
| 143457 | c.1344_1345del (p.Gln449fs) | Rett syndrome |
| 143462 | c.1360_400del (p.Thr454fs) | Rett syndrome |
| 143467 | c.1393C>T (p.Arg465Ter) | Rett syndrome |
| 143487 | c.1495T>C (p.Ter499Arg) | Rett syndrome-related |
| 143491 | c.182C>A (p.Ser61Ter) | Rett syndrome |
| 143492 | c.182C>G (p.Ser61Ter) | Rett syndrome |
| 143497 | c.230C>G (p.Ser77Ter) | Rett syndrome |
| 143499 | c.237del (p.Ser80fs) | Rett syndrome |
| 143500 | c.239C>G (p.Ser80Ter) | Rett syndrome |
| 143502 | c.251_252insT (p.Ala85fs) | Rett syndrome |
| 143503 | c.251dup (p.Ala85fs) | Rett syndrome |
| 143507 | c.269del (p.Ser90fs) | Rett syndrome |
| 143508 | c.279dup (p.Lys94fs) | Rett syndrome |
| 143511 | c.294_295del (p.Ile99fs) | Rett syndrome |
| 143514 | c.312_313insG (p.Pro105fs) | Rett syndrome |
| 143524 | c.337C>T (p.Pro113Ser) | Rett syndrome |
| 143526 | c.338C>G (p.Pro113Arg) | Rett syndrome |
| 143539 | c.370A>T (p.Lys124Ter) | Rett syndrome |
| 143549 | c.408G>C (p.Leu136Phe) | Rett syndrome |
| 143550 | c.408G>T (p.Leu136Phe) | Rett syndrome |
| 143552 | c.416C>T (p.Pro139Leu) | Rett syndrome |
| 143553 | c.418C>T (p.Gln140Ter) | Rett syndrome |
| 11815 | c.844C>T (p.Arg282Ter) | Rett syndrome |
AlphaMissense Predictions
Total missense variants with predictions: ~1100+ protein-level variants
Top 30 Likely-Pathogenic (am_class=“likely_pathogenic”) with highest pathogenicity scores:
| Position | Protein Variant | am_pathogenicity Score | Delta |
|---|---|---|---|
| X:154030916 | K304N | 1.000 | — |
| X:154030912 | R306S | 1.000 | — |
| X:154030920 | I303T | 1.000 | — |
| X:154030916 | K304N | 1.000 | — |
| X:154030907 | K307N | 0.997 | — |
| X:154030902 | R309P | 0.992 | — |
| X:154030923 | P302R | 0.993 | — |
| X:154030911 | R306P | 0.997 | — |
| X:154030926 | L301P | 0.998 | — |
| X:154030898 | E310D | 0.892 | — |
| X:154030381 | E483K | 0.981 | — |
| X:154030903 | R309C/G | 0.980–0.996 | — |
| X:154030905 | T308I | 0.990 | — |
| X:154030915 | K305E | 0.998 | — |
| X:154030918 | K304E | 0.998 | — |
| X:154030880 | K307N | 0.997 | — |
| X:154030899 | E310V | 0.989 | — |
| X:154030921 | I303V | 0.847 | — |
| X:154030370 | S486R | 0.989 | — |
| X:154030380 | E483V | 0.979 | — |
| X:154030374 | V485D | 0.959 | — |
| X:154030402 | D476H | 0.953 | — |
| X:154030380 | E483G | 0.928 | — |
| X:154030374 | V485A | 0.927 | — |
| X:154030449 | D460V | 0.928 | — |
| X:154030450 | D460H | 0.947 | — |
| X:154030375 | V485L | 0.851 | — |
| X:154030371 | S486N | 0.872 | — |
| X:154030389 | P480R | 0.658 | — |
| X:154030401 | D476V | 0.931 | — |
Note: Splice prediction databases (SpliceAI, MaxEntScan) returned no direct entries for MECP2; variant annotations can be accessed through transcript-level databases if needed.
Pathways & Gene Ontology
Reactome Pathways
Total: 11 pathways
| Pathway ID | Pathway Name | Type |
|---|---|---|
| R-HSA-8986944 | Transcriptional Regulation by MECP2 | Normal |
| R-HSA-9022534 | Loss of MECP2 binding ability to 5hmC-DNA | Disease |
| R-HSA-9022535 | Loss of phosphorylation of MECP2 at T308 | Disease |
| R-HSA-9022537 | Loss of MECP2 binding ability to the NCoR/SMRT complex | Disease |
| R-HSA-9022538 | Loss of MECP2 binding ability to 5mC-DNA | Disease |
| R-HSA-9022692 | Regulation of MECP2 expression and activity | Normal |
| R-HSA-9022699 | MECP2 regulates neuronal receptors and channels | Normal |
| R-HSA-9022702 | MECP2 regulates transcription of neuronal ligands | Normal |
| R-HSA-9022707 | MECP2 regulates transcription factors | Normal |
| R-HSA-9022927 | MECP2 regulates transcription of genes involved in GABA signaling | Normal |
| R-HSA-9725371 | Nuclear events stimulated by ALK signaling in cancer | Disease |
MSigDB Gene Sets
Total: 100 gene sets
Includes GO terms (C5), transcription factor targets (C3:TFT), miRNA targets (C3:MIR), curated pathways (C2:CP), cancer modules (C4), and cytogenetic bands (C1).
Gene Ontology Annotations
Biological Process: 68 terms
| GO ID | Term |
|---|---|
| GO:0000122 | Negative regulation of transcription by RNA polymerase II |
| GO:0001662 | Behavioral fear response |
| GO:0001666 | Response to hypoxia |
| GO:0001964 | Startle response |
| GO:0001976 | Nervous system process involved in regulation of systemic arterial blood pressure |
| GO:0002087 | Regulation of respiratory gaseous exchange by nervous system process |
| GO:0006020 | Inositol metabolic process |
| GO:0006357 | Regulation of transcription by RNA polymerase II |
| GO:0006541 | Glutamine metabolic process |
| GO:0006576 | Biogenic amine metabolic process |
| GO:0007219 | Notch signaling pathway |
| GO:0007268 | Chemical synaptic transmission |
| GO:0007416 | Synapse assembly |
| GO:0007420 | Brain development |
| GO:0007585 | Respiratory gaseous exchange by respiratory system |
| GO:0007612 | Learning |
| GO:0007613 | Memory |
| GO:0007616 | Long-term memory |
| GO:0008104 | Intracellular protein localization |
| GO:0008211 | Glucocorticoid metabolic process |
Molecular Function: 14 terms
| GO ID | Term |
|---|---|
| GO:0003676 | Nucleic acid binding |
| GO:0003677 | DNA binding |
| GO:0003682 | Chromatin binding |
| GO:0003714 | Transcription corepressor activity |
| GO:0003723 | RNA binding |
| GO:0003729 | mRNA binding |
| GO:0005515 | Protein binding |
| GO:0008327 | Methyl-CpG binding |
| GO:0010385 | Double-stranded methylated DNA binding |
| GO:0035197 | siRNA binding |
| GO:0060090 | Molecular adaptor activity |
| GO:0140566 | Histone reader activity |
| GO:0140693 | Molecular condensate scaffold activity |
| GO:1990841 | Promoter-specific chromatin binding |
Cellular Component: 10 terms
| GO ID | Term |
|---|---|
| GO:0000785 | Chromatin |
| GO:0000792 | Heterochromatin |
| GO:0005615 | Extracellular space |
| GO:0005634 | Nucleus |
| GO:0005654 | Nucleoplasm |
| GO:0005737 | Cytoplasm |
| GO:0005813 | Centrosome |
| GO:0005829 | Cytosol |
| GO:0045202 | Synapse |
| GO:0098794 | Postsynapse |
Protein interactions & networks
Protein-Protein Interactions
Interaction Summary:
- STRING interactions: ~3,950
- BioGRID interactions: 1,482
- IntAct interactions: 239
- SIGNOR interactions: 49
Top 30 STRING Interactors (by confidence/evidence):
- DNMT1 (DNA cytosine-5-methyltransferase 1) — DNA methylation maintenance
- SIN3A (Sin3 corepressor complex) — Transcriptional repression partner
- HDAC1 (Histone deacetylase 1) — Epigenetic repressor complex
- HDAC2 (Histone deacetylase 2) — Epigenetic repressor complex
- RCOR1 (REST corepressor 1) — BHC complex, chromatin silencing
- NCOR1 (Nuclear receptor corepressor 1) — Transcriptional repression
- SUV39H1 (H3K9 histone methyltransferase) — Heterochromatin formation
- CREB1 (cAMP-responsive element-binding protein) — Transcription factor
- ATRX (Chromatin remodeling helicase) — DNA tandem repeat binding
- CDKL5 (Cyclin-dependent kinase-like 5) — MECP2 phosphorylation partner
- YBX1 (Y-box binding protein 1) — RNA/DNA binding, m5C recognition
- DNMT3A (DNA methyltransferase 3A) — De novo methylation
- FMR1 (Fragile X mental retardation protein) — RNA regulation, neuronal function
- LBR (Delta-14 sterol reductase) — Nuclear lamina anchoring
- DGCR8 (Microprocessor complex subunit) — miRNA biogenesis
- BDNF (Brain-derived neurotrophic factor) — Neuronal signaling
- DNMT3B (DNA methyltransferase 3B) — De novo methylation
- UBE3A (Ubiquitin ligase E3A) — Protein degradation
- GAD1 (Glutamate decarboxylase 1) — GABA synthesis
- PRMT6 (Protein arginine methyltransferase 6) — H3R2 histone methylation
- FOXG1 (Forkhead box G1) — Brain development transcription factor
- SIN3B (Sin3 corepressor complex B) — Transcriptional repression
- UHRF1 (E3 ubiquitin ligase UHRF1) — DNA methylation/histone binding bridge
- H3.2 (Histone H3.2) — Core nucleosome component
- TET1 (Methylcytosine dioxygenase) — 5mC to 5hmC conversion
- GABRB3 (GABA receptor β3) — GABAergic neurotransmission
- H3.3 (Histone H3.3) — Variant histone, active chromatin
- H3-5 (Histone H3.3C) — Core nucleosome component
- H3.1 (Histone H3.1) — Core nucleosome component
- CTCF (Transcriptional repressor) — Chromatin insulator protein
Protein Similarity
ESM2 Embedding Similarity (29 proteins): Top structural similarity includes MBD family proteins, zinc finger proteins, and other methyl-CpG binding domain proteins:
- Q00566, Q9Z2D6, Q9Z2E1, Q9UBB5, Q95LG8 (MBD family orthologs)
- P28667, P29536, P35566, P52926, P52927 (Related methyl-binding proteins)
- Additional zinc finger and chromatin-associated proteins from multiple organisms
Diamond Sequence Similarity (12 proteins):
- Q9Z2D6, Q9Z2E1, Q9Z2D7, Q9Z2D8 (MeCP2 orthologs across species)
- Q00566, Q95LG8, Q9UBB5 (MBD protein family members)
- Q9Z2E2, Q9VGA4, O95243, O95983 (Related methyl-CpG binding proteins)
Key Interaction Networks:
- Chromatin Repression Complex: MECP2 → SIN3A/RCOR1 → HDAC1/2 (core corepressor network)
- DNA Methylation Axis: MECP2 ↔ DNMT1/3A/3B → UHRF1 (maintenance and establishment)
- Histone Modification: MECP2 → SUV39H1/EHMT2/EZH2 → histone variants (H3.1/3.3)
- Neuronal Signaling: MECP2 → BDNF/FMR1/CDKL5 → GABAergic signaling (GAD1/GABRB3)
- Chromatin Remodeling: MECP2 → ATRX/SMARCA4/BRG1 (DNA accessibility regulation)
Transcription factor regulatory data
MECP2 is a transcription corepressor. GO annotations confirm transcription corepressor activity (GO:0003714) with DNA binding and chromatin binding functions. MECP2 primarily represses transcription through methyl-CpG binding and recruitment of corepressor complexes.
Downstream targets
Total: 40+ targets identified in SIGNOR database
TOP 30 targets with regulation type and evidence:
- BDNF — represses (transcriptional regulation, experimentally validated, score 0.47)
- ESR1 — represses (transcriptional regulation, score 0.39)
- GRIN2B — represses (transcriptional regulation, experimentally validated, score 0.35)
- MEF2C — represses (transcriptional regulation, experimentally validated, score 0.35)
- CRH — represses (transcriptional regulation, experimentally validated, score 0.47)
- NOTCH1 — represses (transcriptional regulation, experimentally validated, score 0.29)
- GRIA2 — represses (transcriptional regulation, experimentally validated, score 0.32)
- DLX5 — represses (transcriptional regulation, score 0.38)
- RELN — represses (transcriptional regulation, experimentally validated, score 0.38)
- GAD1 — represses (transcriptional regulation, experimentally validated, score 0.37)
- FKBP5 — represses (transcriptional regulation, experimentally validated, score 0.31)
- RBFOX1 — represses (transcriptional regulation, experimentally validated, score 0.28)
- SGK1 — represses (transcriptional regulation, experimentally validated, score 0.29)
- DLL1 — represses (transcriptional regulation, experimentally validated, score 0.20)
- PTPN1 — represses (transcriptional regulation, experimentally validated, score 0.20)
- AMPA — represses (transcriptional regulation, experimentally validated, score 0.33)
- MGMT — represses (transcriptional regulation, score 0.31)
- IGFBP3 — represses (transcriptional regulation, score 0.25)
- CCND1 — represses (transcriptional regulation, score 0.27)
- ALOX5 — represses (transcriptional regulation, score 0.20)
- ABCB1 — represses (transcriptional regulation, score 0.20)
- TFF1 — represses (transcriptional regulation, score 0.20)
- CREB1 — activates (post-transcriptional, experimentally validated, score 0.53)
- YBX1 — activates activity (binding, experimentally validated, score 0.51)
- DNMT1 — activates activity (binding, experimentally validated, score 0.53)
- TET1 — activates activity (binding, experimentally validated, score 0.43)
- SST — activates (post-transcriptional, experimentally validated, score 0.30)
- GPRIN1 — activates (post-transcriptional, experimentally validated, score 0.30)
- GAMT — activates (post-transcriptional, experimentally validated, score 0.28)
- OPRK1 — activates (post-transcriptional, experimentally validated, score 0.27)
DNA binding motifs
No JASPAR motifs found. MECP2 does not have characterized DNA binding motifs in JASPAR database. MECP2 recognizes methylated CpG dinucleotides (GO:0008327, GO:0010385) rather than sequence-specific DNA motifs, binding through its methyl-CpG binding domain (MBD).
Upstream regulators
Transcription factors that regulate MECP2:
- MEF2C — activates expression (transcriptional regulation, score 0.35)
- miR-132 — represses (post-transcriptional regulation, score 0.40)
Post-translational modifiers (with strong evidence):
- HIPK2 — activates activity (phosphorylation, experimentally validated, score 0.48)
- CDKL5 — modulates (phosphorylation, experimentally validated, score 0.60)
- CHUK — activates activity (phosphorylation, experimentally validated, score 0.20)
Drug & pharmacology data
MECP2 as a drug target: Pre-clinical stage with no approved or clinical-stage drugs
Targeting molecules in ChEMBL: 6 total compounds, all in pre-clinical development (Phase 0)
- CHEMBL1371175 (SID7972424) | Phase 0
- CHEMBL3687963 (US9034574, XVII) | Phase 0
- CHEMBL3687966 (US9034574, XXI) | Phase 0
- CHEMBL3687968 (US9034574, XXIII) | Phase 0
- CHEMBL489770 (N-(4-(pyridin-2-yl)thiazol-2-yl)pyridin-2-amine, GNF-Pf-4773) | Phase 0
- CHEMBL520851 (1-(5-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)naphthalen-2-ol, US9034574, XXII) | Phase 0
Clinical trials: Zero clinical trials found targeting MECP2.
Pharmacogenomics: MECP2 is designated a VIP (Very Important Pharmacogene) in PharmGKB with variant annotations. Four drugs have pharmacogenomic associations with MECP2 variants (affecting drug response/toxicity, not targeting the protein):
- Fluorouracil (197 clinical annotations, 1031 variant annotations)
- Trofinetide (0 clinical annotations, 0 variant annotations) — developmental MECP2-linked agonist
- Cisplatin (123 clinical annotations, 541 variant annotations)
- Mitoxantrone (5 clinical annotations, 24 variant annotations)
Note: No CPIC (Clinical Pharmacogenetics Implementation Consortium) dosing guidelines exist for MECP2.
Expression profiles
Tissue Expression (Bgee)
MECP2 shows ubiquitous expression across 299 conditions with average score of 83.27 (0–100 scale). Top 30 tissues by expression score:
| Rank | Tissue | Score | Quality |
|---|---|---|---|
| 1 | Paraflocculus | 97.92 | Gold |
| 2 | Brodmann area 10 | 97.01 | Gold |
| 3 | Sural nerve | 96.30 | Gold |
| 4 | Frontal pole | 95.89 | Gold |
| 5 | Colonic epithelium | 95.84 | Gold |
| 6 | Middle frontal gyrus | 95.66 | Gold |
| 7 | Cerebellar vermis | 95.09 | Gold |
| 8 | Calcaneal tendon | 94.44 | Gold |
| 9 | Postcentral gyrus | 92.41 | Gold |
| 10 | Tendon | 91.59 | Gold |
| 11 | Parietal lobe | 91.22 | Gold |
| 12 | Blood | 91.07 | Gold |
| 13 | Corpus callosum | 90.35 | Gold |
| 14 | Stomach mucosa | 90.32 | Gold |
| 15 | Bone marrow | 90.24 | Gold |
| 16 | Adrenal tissue | 90.22 | Gold |
| 17 | Granulocytes | 90.17 | Gold |
| 18 | Gastrocnemius | 89.95 | Gold |
| 19 | Leg muscle | 89.87 | Gold |
| 20 | Hindlimb muscle | 89.82 | Gold |
| 21 | Monocytes | 89.49 | Gold |
| 22 | Olfactory nasal mucosa | 89.38 | Gold |
| 23 | Right lung | 89.22 | Gold |
| 24 | Mononuclear leukocytes | 89.00 | Gold |
| 25 | Leukocytes | 88.98 | Gold |
| 26 | Cerebellum | 88.88 | Gold |
| 27 | Parotid gland | 88.87 | Silver |
| 28 | Left ovary | 88.84 | Gold |
| 29 | Tibial artery | 88.73 | Gold |
| 30 | Popliteal artery | 88.73 | Gold |
Tissue-enriched patterns: CNS-predominant (multiple brain regions, cerebellum), nervous tissue (peripheral nerves), and hematopoietic compartments (blood, bone marrow, granulocytes, monocytes).
Cell Type Expression (Bgee)
Identified cell types include:
- Hematopoietic: bone marrow cells (90.24), granulocytes (90.17), monocytes (89.49), mononuclear leukocytes (89.00), leukocytes (88.98)
- Reproductive: secondary oocytes, oocytes, stromal cells of endometrium
- Respiratory: bronchial epithelial cells
Single-cell Expression (SCXA)
Datasets: 3 studies spanning 27,645 total cells with 280 distinct clusters
| Dataset | Cell Type/Condition | Cell Count |
|---|---|---|
| Tabula Sapiens (Smart-seq2) | Multi-tissue survey | 27,051 |
| E-MTAB-7381 | AIRE+ dendritic cells (tonsillitis) | 384 |
| E-MTAB-7606 | CD8+ T cells (influenza-specific, baseline/acute/memory) | 210 |
Expression metric: Max mean expression 587.84 TPM; average 8.82 TPM across clusters. Gene marked as cluster-defining (marker) in all 3 experiments.
Disease associations
Mendelian / Monogenic Diseases
| Disease | Gene ID | Disease ID | Inheritance | Evidence |
|---|---|---|---|---|
| Rett syndrome | MECP2 | OMIM:312750 / ORPHANET:778 / MONDO:0010726 | X-linked dominant | Definitive |
| Severe neonatal-onset encephalopathy with microcephaly | MECP2 | OMIM:300673 / ORPHANET:209370 / MONDO:0010397 | X-linked dominant | Definitive |
| Syndromic X-linked intellectual disability Lubs type | MECP2 | OMIM:300260 / MONDO:0010283 | X-linked recessive | Definitive |
| Chromosome Xq28 duplication syndrome | MECP2 | OMIM:300815 / ORPHANET:1762 | X-linked dominant | Definitive |
| X-linked intellectual disability-psychosis-macroorchidism syndrome | MECP2 | ORPHANET:3077 / MONDO:0010235 | X-linked dominant | Supportive |
| Atypical Rett syndrome | MECP2 | ORPHANET:3095 / MONDO:0017746 | Autosomal dominant | Supportive |
| Non-syndromic X-linked intellectual disability | MECP2 | ORPHANET:777 / MONDO:0019181 | X-linked dominant | Supportive |
Phenotype Associations (Top 30 HPO Terms)
| HPO ID | Phenotype | HPO ID | Phenotype |
|---|---|---|---|
| HP:0001249 | Intellectual disability | HP:0001298 | Encephalopathy |
| HP:0001250 | Seizure | HP:0001250 | Seizure |
| HP:0001252 | Hypotonia | HP:0001332 | Dystonia |
| HP:0001263 | Global developmental delay | HP:0001336 | Myoclonus |
| HP:0000252 | Microcephaly | HP:0001337 | Tremor |
| HP:0001257 | Spasticity | HP:0001417 | X-linked inheritance |
| HP:0000717 | Autism | HP:0001508 | Failure to thrive |
| HP:0001288 | Gait disturbance | HP:0000729 | Autistic behavior |
| HP:0001344 | Absent speech | HP:0000733 | Motor stereotypy |
| HP:0000750 | Delayed speech and language development | HP:0001251 | Ataxia |
| HP:0001256 | Mild intellectual disability | HP:0001258 | Spastic paraplegia |
| HP:0002015 | Dysphagia | HP:0000718 | Aggressive behavior |
| HP:0000737 | Irritability | HP:0001347 | Hyperreflexia |
| HP:0000739 | Anxiety | HP:0001266 | Choreoathetosis |
| HP:0000713 | Agitation | HP:0001300 | Parkinsonism |
Complex Disease / GWAS Associations
| Trait/Disease | Effect Size (p-value) | MECP2 Role |
|---|---|---|
| Systemic lupus erythematosus | 2.0 × 10⁻¹⁵ | Significant association |
| Non-albumin protein levels | 5.0 × 10⁻⁹ | Genetic variant association |