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MECP2 (methyl CpG binding protein 2 (Rett syndrome)) is a gene that provides instructions for making its protein product, MECP2, also referred to as MeCP2. MECP2 appears to be essential for the normal function of nerve cells. The protein seems to be particularly important for mature nerve cells, where it is present in high levels. The MeCP2 protein is likely to be involved in turning off ("repressing" or "silencing") several other genes. This prevents the genes from making proteins when they are needed. Recent work has shown that MeCP2 can also activate other genes.[1]

The MeCP2 protein binds to forms of DNA that have been methylated. The MeCP2 protein then interacts with other proteins to form a complex that turns off the gene. Methylation is a chemical alteration made to a "cytosine" (C) when it occurs in a particular DNA sequence, "CpG". Many genes have CpG islands, which frequently occur near the beginning of the gene. MECP2 does not bind to these islands in most cases, as they are not methylated. The expression of a few genes may be regulated through methylation of their CpG island, and MECP2 may play a role in a subset of these. Researchers have not yet determined which genes are targeted by the MeCP2 protein, but such genes are probably important for the normal function of the central nervous system. However, the first large-scale mapping of MECP2 binding sites in neurons found that only 6% of the binding sites are in CpG islands, and that 63% of MECP2-bound promoters are actively expressed and only 6% are highly methylated, indicating that MECP2's main function is something other than silencing methylated promoters.[2]

Once bound, MeCP2 will condense the chromatin structure, form a complex with histone deacetylases (HDAC), or block transcription factors directly. More recent studies have demonstrated that MeCP2 can also function as a transcriptional activator, through recruiting the transcription factor CREB1. This was an unexpected finding which indicates that MeCP2 is a key transcriptional regulator with dual functions on gene expression. In fact, the majority of gene that are regulated by MeCP2 are activated rather than repressed [3]. Further studies have shown MeCP2 may be able to bind directly to un-methylated DNA in some instances.[4] MeCP2 has been implicated in regulation of imprinted genes and loci that include UBE3A and DLX5.[5] DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells. MECP2 gene mutations are the cause of some cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of mental retardation in females.[6] The MECP2 gene is located on the long (q) arm of the X chromosome in band 28 ("Xq28"), from base pair 152,808,110 to base pair 152,878,611.

Protein Structure

MeCP2 is part of a family of methyl-CpG-binding domain proteins (MBD), but possesses its own unique differences which help set it apart from the group. It has two functional domains:

  • a methyl-cytosine-binding domain (MBD) composed of 85 amino acids; and
  • a transcriptional repression domain (TRD) composed of 104 amino acids

The MBD domain forms a wedge and attaches to the methylated CpG sites on the DNA strands. The TRD region then reacts with SIN3A to recruit histone deacetylases (HDAC) [7]. There are also unusual, repetitive sequences found at the carboxyl terminus. This region is closely related to the fork head family, at the amino acid level [8].


MeCP2 protein is found in all cells in the body, including the brain, acting as a transcriptional repressor and activator, depending on the context. In the brain, it is found in high concentrations in the neurons and is associated with maturation of the central nervous system (CNS) and in forming synaptic contacts.[9]

Role in Disease

Rett syndrome is caused by mutations in the MECP2 gene. Several types of mutations have been identified in people with Rett syndrome. These mutations include changes in single base pairs (the building material of DNA), insertions or deletions of DNA in the gene, and changes that affect how the gene is processed into a protein. Mutations in the gene alter the structure of the MeCP2 protein or lead to reduced amounts of the protein. As a result, the protein is unable to bind to DNA or turn other genes on or off. Genes that are normally repressed by MeCP2 remain active and continue to make large amounts of particular proteins when they are not needed. Other genes that are normally activated by MeCP2 remain inactive and thus unable to make protein products. This defect probably disrupts the normal functioning of nerve cells, leading to the signs and symptoms of Rett syndrome.

This disease is mainly found in girls with a prevalence of around 1 in every 10,000. Patients are born normal, but after about six months to a year and half, speech and motor function capabilities start to decrease. This is followed by seizures, growth retardation, autistic behavior and cognitive and motor impairment.[10] This is a X-linked dominant disease that is found predominatley affecting the paternal X chromosome. It has been linked to male lethality, due to its prevalence in females, but in rare cases some males can also be affected by Rett Syndrome [11].

Mutations in the MECP2 gene have also been identified in people with several other disorders affecting the central nervous system. For example, MECP2 mutations are associated with some cases of moderate to severe X-linked mental retardation. Mutations in the gene have also been found in males with severe brain dysfunction (neonatal encephalopathy) who live only into early childhood. In addition, several people with features of both Rett syndrome and Angelman syndrome (a condition characterized by mental retardation, problems with movement, and inappropriate laughter and excitability) have mutations in the MECP2 gene. Lastly, MECP2 mutations or changes in the gene's activity have been reported in some cases of autism (a developmental disorder that affects communication and social interaction).

More recent studies reported genetic polymorphisms in the MeCP2 genes in patients with systemic lupus erythematosus (SLE) [12]. SLE is an systemic autoimmune disease that can affect multiple organs. MeCP2 polymorphisms have been reported so far in European-derived and Asian lupus patients.


  1. Chahrour M, et al. (2008). MeCP2, a key contributor to neurological disease, activates and represses transcription. Science.
  2. Yasui DH, Peddada S, Bieda MC et al. (2007). Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes. Proc Natl Acad Sci U S A.
  3. Chahrour M et a. Science 2008 PMID: 18511691
  4. Chromatin Compaction by Human MeCP2. Georgel et al., [1]
  5. LaSalle JM (2006). The odyssey of MeCP2 and parental imprinting. Epigenetics 2 (1): 5–10.
  6. Entrez Gene: MECP2 methyl CpG binding protein 2 (Rett syndrome).
  7. Wakefield et al., [2]
  8. Paul A. Wade, [3]
  9. Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Jaenisch R., Luikenhuis S. et al., [4]
  10. Caballero IM, Hendrich B (2005). MeCP2 in neurons: closing in on the causes of Rett syndrome. Hum Mol Genet 14 (Review 1): R19–26.
  11. Samaco RC, Nagarajan RP, Braunschweig D, LaSalle JM (2004). Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders. Hum Mol Genet 13 (6): 629–39.
  12. Sawalha AH et al. Common variants within MECP2 confer risk of systemic lupus erythematosus. PLoSOne 2008 5;3(3):e1727(

Further reading

  • Chahrour M, Zoghbi HY (2007). The story of Rett syndrome: from clinic to neurobiology. Neuron 56 (3): 422–37.
  • Carney RM, Wolpert CM, Ravan SA, Shahbazian M, Ashley-Koch A, Cuccaro ML, Vance JM, Pericak-Vance MA (2003). Identification of MeCP2 mutations in a series of females with autistic disorder. Pediatr Neurol 28 (3): 205–11.
  • Kerr AM, Ravine D (2003). Review article: breaking new ground with Rett syndrome. J Intellect Disabil Res 47 (Pt 8): 580–7.
  • Neul JL, Zoghbi HY (2004). Rett syndrome: a prototypical neurodevelopmental disorder. Neuroscientist 10 (2): 118–28.
  • Schanen C, Houwink EJ, Dorrani N, Lane J, Everett R, Feng A, Cantor RM, Percy A (2004). Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome. Am J Med Genet A 126 (2): 129–40.
  • Van den Veyver IB, Zoghbi HY (2001). Mutations in the gene encoding methyl-CpG-binding protein 2 cause Rett syndrome. Brain Dev 23 Suppl 1: S147–51.
  • Webb T, Latif F (2001). Rett syndrome and the MECP2 gene. J Med Genet 38 (4): 217–23.
  • Shahbazian MD, Zoghbi HY (2003). Rett syndrome and MeCP2: linking epigenetics and neuronal function.. Am. J. Hum. Genet. 71 (6): 1259–72.
  • Moog U, Smeets EE, van Roozendaal KE, et al. (2003). Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2).. Eur. J. Paediatr. Neurol. 7 (1): 5–12.
  • Miltenberger-Miltenyi G, Laccone F (2004). Mutations and polymorphisms in the human methyl CpG-binding protein MECP2.. Hum. Mutat. 22 (2): 107–15.
  • Weaving LS, Ellaway CJ, Gécz J, Christodoulou J (2006). Rett syndrome: clinical review and genetic update.. J. Med. Genet. 42 (1): 1–7.
  • Bapat S, Galande S (2005). Association by guilt: identification of DLX5 as a target for MeCP2 provides a molecular link between genomic imprinting and Rett syndrome.. Bioessays 27 (7): 676–80.
  • Zlatanova J (2005). MeCP2: the chromatin connection and beyond.. Biochem. Cell Biol. 83 (3): 251–62.
  • Kaufmann WE, Johnston MV, Blue ME (2006). MeCP2 expression and function during brain development: implications for Rett syndrome's pathogenesis and clinical evolution.. Brain Dev. 27 Suppl 1: S77–S87.
  • Armstrong DD (2006). Can we relate MeCP2 deficiency to the structural and chemical abnormalities in the Rett brain?. Brain Dev. 27 Suppl 1: S72–S76.
  • Santos M, Coelho PA, Maciel P (2006). Chromatin remodeling and neuronal function: exciting links.. Genes Brain Behav. 5 Suppl 2: 80–91.
  • Bienvenu T, Chelly J (2006). Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized.. Nat. Rev. Genet. 7 (6): 415–26.
  • Francke U (2007). Mechanisms of disease: neurogenetics of MeCP2 deficiency.. Nature clinical practice. Neurology 2 (4): 212–21.

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