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MECP2
methyl-CpG binding protein 2
The MECP2 gene provides instructions for producing the MeCP2 protein, a crucial regulator of gene activity, particularly abundant and important for function in brain cells. MECP2 is an X-linked gene that codes for the methyl-CpG binding protein 2.
MECP2 is located on the long (q) arm of chromosome X, at band Xq28. Arm ratio per GRCh38 - banding schematic.
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Overview
The MECP2 gene, or methyl-CpG binding protein 2, is a significant gene involved in regulating gene expression throughout the body, with a particularly high concentration and critical role in the brain. It is located on the X chromosome and is associated with a range of neurodevelopmental conditions.
The protein encoded by MECP2, known as MeCP2, helps manage the packaging of DNA within chromosomes, thereby influencing which genes are turned on or off. Its proper function is vital for the development and maintenance of brain cells, including neurons.
What the gene does
The MeCP2 protein, encoded by the MECP2 gene, is a key regulator of gene activity. It achieves this by modifying chromatin, which is the complex structure of DNA and proteins that forms chromosomes. By altering chromatin structure, MeCP2 can influence the expression of numerous genes.
Within the brain, MeCP2 is highly expressed and plays a crucial role in the proper functioning of nerve cells, known as neurons. It is thought to be involved in maintaining the synaptic connections between neurons, which are essential for cell-to-cell communication. Many genes regulated by MeCP2 are known to be important for normal brain function and synaptic integrity.
Additionally, MeCP2 may contribute to the processing of messenger RNA (mRNA) molecules. Through a process called alternative splicing, MeCP2 can help cut and rearrange mRNA, leading to the production of different versions of proteins. This alternative splicing is particularly important in the brain for neuronal communication and the function of other brain cell types.
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Chromosome location
The MECP2 gene is found on the long arm of the X chromosome at position Xq28. As an X-linked gene, its inheritance pattern means that conditions associated with MECP2 often affect males and females differently, with males typically experiencing more severe symptoms due to having only one X chromosome.
Protein structure
The MeCP2 protein consists of 486 amino acids. It features several distinct regions and domains crucial for its function. The protein begins with a Disordered region spanning amino acids 1-119. Following this, the MBD (Methyl-CpG Binding Domain) is located between amino acids 90 and 162, which is responsible for binding to methylated DNA. Another Disordered region follows from amino acids 147 to 275.
Further functional segments include two A.T hook DNA binding motifs: A.T hook 1 from amino acids 185-197 and A.T hook 2 from amino acids 265-277. The protein also contains regions for interaction with other proteins, specifically an Interaction with NCOR2 region from amino acids 269-309 and an Interaction with TBL1XR1 region from amino acids 285-309. The protein concludes with a long Disordered region from amino acids 324-486.
Key variants
Variants within the MECP2 gene can alter the structure or function of the MeCP2 protein, leading to disrupted gene regulation and neurological impairment. These genetic changes can range from single base pair alterations to larger deletions or duplications within the gene. The specific type and location of a variant can influence the resulting clinical presentation and severity.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1001C>T | p.Pro334Leu | Pathogenic | ★★★☆ | Rett syndrome |
c.1174_1199del | p.Val392fs | Pathogenic | ★★★☆ | not provided |
c.1200_1243del | p.Pro400_Pro401insTer | Pathogenic | ★★★☆ | Rett syndrome, zappella variant |
c.1490_1493del | p.Val497fs | Pathogenic | ★★★☆ | Rett syndrome |
c.1497A>G | p.Ter499Trp | Pathogenic | ★★★☆ | not specified |
c.334C>G | p.Leu112Val | Pathogenic | ★★★☆ | Rett syndrome |
c.337C>T | p.Pro113Ser | Pathogenic | ★★★☆ | Rett syndrome |
c.338C>G | p.Pro113Arg | Pathogenic | ★★★☆ | Angelman syndrome |
c.380G>A | p.Arg127His | Pathogenic | ★★★☆ | not provided |
c.400G>A | p.Val134Met | Pathogenic | ★★★☆ | Rett syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the MECP2 gene are linked to several neurodevelopmental disorders, including Rett syndrome, which primarily affects females and causes issues with communication, learning, and coordination. Males are predominantly affected by conditions such as MECP2 duplication syndrome, characterised by intellectual disability, developmental delay, and seizures, and MECP2-related severe neonatal encephalopathy, which can cause microcephaly, movement disorders, and breathing problems. PPM-X syndrome, also linked to MECP2 variants, presents with intellectual disability and movement abnormalities.
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Inheritance pattern
Conditions caused by pathogenic MECP2 variants typically follow x-linked inheritance.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
UK clinical status
The MECP2 gene is included in several expert-curated panels within the NHS Genomic Medicine Service's PanelApp. It is rated 'green' for conditions such as DDG2P, Early onset or syndromic epilepsy, Intellectual disability, and Severe microcephaly (R88). This signifies strong evidence for its association with these conditions, supporting its inclusion in diagnostic genetic testing within the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the MECP2 gene?
The MECP2 gene provides instructions for making the MeCP2 protein, which is vital for regulating gene activity, especially in the brain. It helps manage how DNA is packaged and expressed, influencing the development and function of nerve cells.
What conditions are associated with MECP2 variants?
Variants in the MECP2 gene are associated with several neurodevelopmental conditions, including Rett syndrome, MECP2 duplication syndrome, MECP2-related severe neonatal encephalopathy, and PPM-X syndrome.
Why is MECP2 particularly important in the brain?
MeCP2 protein is highly concentrated in brain cells, where it plays a critical role in maintaining connections between neurons (synapses) and influencing the expression of genes essential for normal brain function and communication between nerve cells.
References
- Signorini C, De Felice C, Leoncini S. MECP2 Duplication Syndrome: Evidence of Enhanced Oxidative Stress. A Comparison with Rett Syndrome. PloS one. 2016. PMID: 26930212
- Lyst MJ, Bird A. Rett syndrome: a complex disorder with simple roots. Nature reviews. Genetics. 2015. PMID: 25732612
- Viana MC, Menezes AN, Moreira MA. MECP2, a gene associated with Rett syndrome in humans, shows conserved coding regions, independent Alu insertions, and a novel transcript across primate evolution. BMC genetics. 2015. PMID: 26148505
- Lombardi LM, Baker SA, Zoghbi HY. MECP2 disorders: from the clinic to mice and back. The Journal of clinical investigation. 2015. PMID: 26237041
- Adkins NL, Georgel PT. MeCP2: structure and function. Biochemistry and cell biology = Biochimie et biologie cellulaire. 2011. PMID: 21326358
- Samaco RC, Neul JL. Complexities of Rett syndrome and MeCP2. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2011. PMID: 21632916
- McGraw CM, Samaco RC, Zoghbi HY. Adult neural function requires MeCP2. Science (New York, N.Y.). 2011. PMID: 21636743
- Skene PJ, Illingworth RS, Webb S. Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Molecular cell. 2010. PMID: 20188665
- Gonzales ML, LaSalle JM. The role of MeCP2 in brain development and neurodevelopmental disorders. Current psychiatry reports. 2010. PMID: 20425298
- Lugtenberg D, Kleefstra T, Oudakker AR. Structural variation in Xq28: MECP2 duplications in 1% of patients with unexplained XLMR and in 2% of male patients with severe encephalopathy. European journal of human genetics : EJHG. 2009. PMID: 18985075
- Chahrour M, Zoghbi HY. The story of Rett syndrome: from clinic to neurobiology. Neuron. 2007. PMID: 17988628
- Van Esch H, Bauters M, Ignatius J. Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. American journal of human genetics. 2005. PMID: 16080119
- Young JI, Hong EP, Castle JC. Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. Proceedings of the National Academy of Sciences of the United States of America. 2005. PMID: 16251272
- Neul JL, Zoghbi HY. Rett syndrome: a prototypical neurodevelopmental disorder. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. 2004. PMID: 15070486
- Carney RM, Wolpert CM, Ravan SA. Identification of MeCP2 mutations in a series of females with autistic disorder. Pediatric neurology. 2003. PMID: 12770674
- Amir RE, Van den Veyver IB, Wan M. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature genetics. 1999. PMID: 10508514