MECP2

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 not needed.

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.^[1]

Once bound, MeCP2 will condense the chromatin structure, form a complex with histone deacetylases (HDAC), or block transcription factors directly. Further studies have shown MeCP2 may be able to bind directly to un-methylated DNA in some instances.^[2] MeCP2 has been implicated in regulation of imprinted genes and loci that include UBE3A and DLX5.^[3]

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, but is essential for embryonic development. 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.^[4]

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.

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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:

• an 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) ^[5]. 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 ^[6].

Function

MeCP2 protein is found in all cells in the body, including the brain, acting as transcriptional repressor. 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.^[7]

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 off other genes. Genes that are normally regulated by MeCP2 remain active and continue to make large amounts of particular proteins when they are not needed. 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.^[8] 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 ^[9].

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).

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