MECP2

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MECP2 (methyl CpG binding protein 2 (Rett syndrome)) is a gene that encodes the protein 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. Recent work has shown that MECP2 can also activate other genes. 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.

DNA methylation is a major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2 (this protein), 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 dispensable in stem cells. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of mental retardation in females.

Function

MECP2 protein is found in all cells in the body, including the brain, acting as a transcriptional repressor and activator, depending on the context. However, the idea that MECP2 functions as an activator is relatively new and remains controversial. In the brain, it is found in high concentrations in neurons and is associated with maturation of the central nervous system (CNS) and in forming synaptic contacts.

Mechanism of action

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.

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 may also function as a transcriptional activator, through recruiting the transcription factor CREB1. This was an unexpected finding which suggests that MeCP2 is a key transcriptional regulator with potentially dual roles in gene expression. In fact, the majority of genes that are regulated by MeCP2 appear to be activated rather than repressed. However, it remains controversial whether MeCP2 regulates these genes directly or whether these changes are secondary in nature. Further studies have shown MeCP2 may be able to bind directly to un-methylated DNA in some instances. MeCP2 has been implicated in regulation of imprinted genes and loci that include UBE3A and DLX5.

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). 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.

Role in disease

The role of MECP2 in disease is primarily associated with either a loss of function (under expression) of the MECP2 gene as in Rett syndrome or in a gain of function (over expression) as in MECP2 Duplication Syndrome. Many mutations have been associated with loss of expression of the MECP2 gene and have been identified in Rett syndrome patients. These mutations include changes in single DNA base pairs (SNP), insertions or deletions of DNA in the MECP2 gene, and changes that affect how the gene information is processed into a protein (RNA splicing). 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 when their products are not needed. Other genes that are normally activated by MeCP2 remain inactive leading to a lack of gene product. This defect probably disrupts the normal functioning of nerve cells, leading to the signs and symptoms of Rett syndrome.

Rett syndrome is mainly found in girls with a prevalence of around 1 in every 10,000. Patients are born with very hard to find signs of a disorder, 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 and cognitive and motor impairment. The MECP2 locus is X-linked and the disease-causing alleles are dominant. Due to its prevalence in females, it has been linked to male lethality, or to a predominant transmission with the paternal X chromosome; nevertheless, in rare cases some males can also be affected by Rett Syndrome. Males with gene duplications of MECP-2 at the Xq28 locus are also at risk for recurrent infections & meningitis in infancy.

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). SLE is a systemic autoimmune disease that can affect multiple organs. MeCP2 polymorphisms have been reported so far in European-derived and Asian lupus patients.

The genetic loss of MECP2 has been identified as changing the properties of cells in the locus ceruleus the exclusive source of noradrenergic innervation to the cerebral cortex and hippocampus.

Researchers have concluded that "Because these neurons are a pivotal source of norepinephrine throughout the brainstem and forebrain and are involved in the regulation of diverse functions disrupted in Rett syndrome, such as respiration and cognition, we hypothesize that the locus ceruleus is a critical site at which loss of MECP2 results in CNS dysfunction."

Interactive pathway map

Click on genes, proteins and metabolites below to visit related articles.

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MECP2 and associated Rett Syndrome edit

Interactions

MECP2 has been shown to interact with SKI protein and Nuclear receptor co-repressor 1. In neuronal cells the MECP2 mRNA is thought to interact with miR-132, which silences the expression of the protein. This forms part of a homeostatic mechanism that could regulate MECP2 levels in the brain.

MeCP2 and Hormones

MeCP2 in the developing rat brain regulates important social development in a sexually dimorphic manner. MeCP2 levels are different between males and females in the developing rat brain 24 hours after birth within the amygdala and hypothalamus, but this difference is no longer observed 10 days after birth. Specifically, males express less MeCP2 than females, and this aligns with the steroid-sensitive time period of the neonatal rat brain. Reductions in MeCP2 with Small interfering RNA (siRNA) during the first few days of life reduce male levels of juvenile social play behavior to female typical levels, but do not affect female juvenile play behavior.

MeCP2 is important in organizing hormone-related behaviors and sex differences in the developing rat amygdala. MeCP2 appears to regulate arginine vasopressin (AVP) and androgen receptor (AR) production in male rats but not in females. Vasopressin is known to regulate many social behaviors including pair bonding and social recognition. While male rats typically have higher levels of vasopressin in the amygdala, MeCP2 reduction during the first 3 days of life causes a lasting reduction of vasopressin to female typical levels in this brain region that lasted through adulthood. Male rats with reduced MeCP2 levels also show a significant reduction of AR at two weeks following infusion, but this effect is gone by adulthood.

Early life stress

MeCP2 monitors the response to early life stress. Early life stress is correlated with hyper-phosphorylation of the MeCP2 protein in the paraventricular nucleus of the hypothalamus. This thus causes a reduced occupancy of MeCP2 at the AVP gene’s promotor region, and therefore elevated levels of AVP. Vasopressin is a primary hormone involved in the Hypothalmic-Pituitary-Adrenal Axis, the connectivity in the brain that regulates processing of and reaction to stress. Decreased functioning of the MeCP2 protein thus upregulates the neuronal stress response.

Further reading

• Chahrour M, Zoghbi HY (2007). "The story of Rett syndrome: from clinic to neurobiology". Neuron. 56 (3): 422–37. doi:10.1016/j.neuron.2007.10.001. PMID 17988628.
• 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. doi:10.1016/S0887-8994(02)00624-0. PMID 12770674.
• Kerr AM, Ravine D (2003). "Review article: breaking new ground with Rett syndrome". J Intellect Disabil Res. 47 (Pt 8): 580–7. doi:10.1046/j.1365-2788.2003.00506.x. PMID 14641805.
• Neul JL, Zoghbi HY (2004). "Rett syndrome: a prototypical neurodevelopmental disorder". Neuroscientist. 10 (2): 118–28. doi:10.1177/1073858403260995. PMID 15070486.
• 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. doi:10.1002/ajmg.a.20571. PMID 15057977.
• 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. doi:10.1016/S0387-7604(01)00376-X. PMID 11738862.
• Webb T, Latif F (2001). "Rett syndrome and the MECP2 gene". J Med Genet. 38 (4): 217–23. doi:10.1136/jmg.38.4.217. PMC 1734858. PMID 11283201.
• Shahbazian MD, Zoghbi HY (2003). "Rett syndrome and MeCP2: linking epigenetics and neuronal function". Am. J. Hum. Genet. 71 (6): 1259–72. doi:10.1086/345360. PMC 378559. PMID 12442230.
• 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. doi:10.1016/S1090-3798(02)00134-4. PMID 12615169.
• Miltenberger-Miltenyi G, Laccone F (2004). "Mutations and polymorphisms in the human methyl CpG-binding protein MECP2". Hum. Mutat. 22 (2): 107–15. doi:10.1002/humu.10243. PMID 12872250.
• Weaving LS, Ellaway CJ, Gécz J, Christodoulou J (2006). "Rett syndrome: clinical review and genetic update". J. Med. Genet. 42 (1): 1–7. doi:10.1136/jmg.2004.027730. PMC 1735910. PMID 15635068.
• 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. doi:10.1002/bies.20266. PMID 15954098.
• Zlatanova J (2005). "MeCP2: the chromatin connection and beyond". Biochem. Cell Biol. 83 (3): 251–62. doi:10.1139/o05-048. PMID 15959553.
• 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. doi:10.1016/j.braindev.2004.10.008. PMID 16182491.
• 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. doi:10.1016/j.braindev.2004.10.009. PMID 16182497.
• Santos M, Coelho PA, Maciel P (2006). "Chromatin remodeling and neuronal function: exciting links". Genes, Brain and Behavior. 5 (Suppl 2): 80–91. doi:10.1111/j.1601-183X.2006.00227.x. PMID 16681803.
• Bienvenu T, Chelly J (2006). "Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized". Nature Reviews Genetics. 7 (6): 415–26. doi:10.1038/nrg1878. PMID 16708070.
• Francke U (2007). "Mechanisms of disease: neurogenetics of MeCP2 deficiency". Nature Clinical Practice Neurology. 2 (4): 212–21. doi:10.1038/ncpneuro0148. PMID 16932552.

External links

• International Rett Syndrome Foundation
• Rett UK Support and Research Charity
• Rett Syndrome Research Trust
• Template:Ensembl
• GeneCard
• RettBASE: IRSA MECP2 Variation Database
• GeneReview/NIH/UW entry on MECP2-Related Disorders
• GeneReviews/NCBI/NIH/UW entry on MECP2 Duplication Syndrome
• UK Site for Families Affected by MECP2.
• Site for Families Affected by MECP2.