Disease relevance of MECP2

• MECP2 is highly mutated in X-linked mental retardation [1].
• Rett syndrome, an X-linked dominant disorder caused by MECP2 mutations, and Angelman syndrome, an imprinted disorder caused by maternal 15q11-q13 or UBE3A deficiency, have phenotypic and genetic overlap with autism [2].
• In addition, ectopic expression of the MECP2 conferred a growth advantage to human prostate cancer cells [3].
• Mutational analysis of MECP2 was performed in mentally retarded female patients who were negative for FMR1 CGG repeat expansion, in male and female patients with clinical features suggestive of either Angelman or Prader-Willi syndrome without methylation defects on chromosome 15q11-q13 [4].
• Although the phenotype of CDKL5 mutation is similar to Rett syndrome caused by MECP2 mutation, the former is characterized by early-onset seizures and association with West syndrome [5].

Psychiatry related information on MECP2

• Mutations in MECP2 are associated with Rett syndrome, an X-linked neurodevelopmental disorder [6].
• Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males [7].
• Mutation analysis of the coding sequence of the MECP2 gene in infantile autism [8].
• Rett syndrome (RTT) is unique among genetic, chromosomal and other developmental disorders because of its extreme female gender bias, early normal development, and subsequent developmental regression with loss of motor and language skills [9].
• Except for Rett syndrome--attributable in most affected individuals to mutations of the methyl-CpG-binding protein 2 (MeCP2) gene--the other PDD subtypes (autistic disorder, Asperger disorder, disintegrative disorder, and PDD Not Otherwise Specified [PDD-NOS]) are not linked to any particular genetic or nongenetic cause [10].

High impact information on MECP2

• Testing for association between MeCP2 and the brahma-associated SWI/SNF chromatin-remodeling complex [11].
• A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome [12].
• Most RTT patients are heterozygous for mutations in the X-linked gene MECP2 (refs. 3-12), encoding a protein that binds to methylated sites in genomic DNA and facilitates gene silencing [13].
• Here we show that Mecp2-deficient mice exhibit phenotypes that resemble some of the symptoms of RTT patients [14].
• In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother [15].

Chemical compound and disease context of MECP2

• Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein [16].
• Interestingly, more malignant MDA-MB- 231 human breast cancer cells have a more prominent loss of DNA methylation accompanied by altered expression of maintenance DNA methyltransferase DNMT1, methyl-binding proteins MeCP2 and MBD2, decreased trimethylation of lysine 20 of histone H4 and hyperacetylation of histone H4 compared to MCF-7 cells [17].
• CONCLUSION: Irrespective of the MECP2 genotype, 5MTHF transfer to the CNS is reduced in Rett syndrome [18].
• Mutations of the methylated DNA binding protein MeCP2, a multifunctional protein that is thought to transmit epigenetic information encoded as methylated CpG dinucleotides to the transcriptional machinery, give rise to the debilitating neurodevelopmental disease Rett syndrome (RTT) [19].

Biological context of MECP2

• Comparison of the clinical features in these patients and in a previously reported patient enables refinement of the genotype-phenotype correlation and strongly suggests that increased dosage of MECP2 results in the MR phenotype [7].
• However, RNA interference of endogenous MECP2 does not induce the expression of the inactive SYBL1 alleles, suggesting that its silencing activity can be replaced by the other methyl-binding proteins [20].
• RESULTS: We identified mainly silent polymorphisms within the MECP2 gene, together with four sequence alterations of unknown significance, i.e. three missense mutations (T197M, T228S, and P376S) and one substitution at position -19 in intron 3 (378-19delT) [21].
• CONCLUSIONS: These results confirm that MECP2 mutations in males are far more rare than initially thought and call for a careful evaluation of the pathogenicity of the MECP2 missense mutations identified in mentally retarded males before genetic counseling is proposed to the relatives [21].
• Mutations in MECP2 appear to give a growth disadvantage to both neuronal and lymphoblast cells, often resulting in skewing of X inactivation that may contribute to the large degree of phenotypic variation [22].

Anatomical context of MECP2

• As female somatic cells are mosaic for expression of mutant MECP2, we performed single cell cloning of T lymphocytes from four RTT patients with MECP2 mutations to isolate cells expressing mutant MECP2 [23].
• Mutations in MECP2 are primarily de novo events in the male germ line and thus lead to an excess of affected females [24].
• However, there was no protein expression for MBD2 and MeCP2 in cancer cell lines and cancer tissues [25].
• In HeLa cells, quantitative chromatin immunoprecipitation assays indicated that MBD2 is associated with the methylated region, while MeCP2 and MBD1 were not detected at this locus [26].
• However, conditional mouse mutants with selective loss of Mecp2 in the brain develop clinical manifestations similar to RTT, indicating that MECP2 is exclusively required for central nervous system function [27].

Associations of MECP2 with chemical compounds

• Our preliminary results suggest that reduction in N-acetylaspartate/total creatine ratio may not be related to the MECP2 mutation [28].
• Bisulfite genomic sequencing demonstrated that the majority of MeCP2 binding occurred in DNA sequences with methylation-associated silencing [29].
• Treatment of cancer cell lines with proteasome inhibitor (MG-132) did not restore expression of MBD2 and MeCP2 proteins [25].
• Illegitimate recombination resulting in deletion at a substantial proportion of the shared MECP2 sites is enhanced by repeated guanosine (G) DNA sequences in the antisense direction, consistent with reports at other gene loci that polypurine (multiple guanosine or adenosine (A)) basepairs enhance sequence deletion [30].
• RESULTS: Two patients without and two with mutations of the MECP2 gene had normal values for red blood cell folate, serum folate, homocysteine, and methionine [18].

Physical interactions of MECP2

• AIM: To explore the effect of DNA methyltransferase, demethylase and methyl-CpG binding protein MeCP2 on the expressions and methylation of hMSH2 and proto-oncogene in human gastric cancer [31].
• We further demonstrate that MeCP2 actually binds to the highly methylated exon 1 of the GFAP gene in neurons [32].
• Global DNA hypomethylation was paralleled by reduction in the levels of maintenance (DNMT1) and de novo (DNMT3a and 3b) DNA methyltransferases and methyl-binding protein MeCP2 [33].
• The methyl-CpG-binding protein MeCP2 appears to reside in a complex with histone deacetylase activity [34].
• Importantly, enforced T-bet expression led to dissociation of the mSin3a corepressor from the endogenous, chromatinized IFN-gamma promoter without decreasing loading of the methyl-CpG binding protein MeCP2 [35].

Regulatory relationships of MECP2

• The results of this study demonstrate that MBD2 gene is expressed in all samples and MeCP2 gene is expressed in all cancer cell lines but not in BPH-1 cell line [25].
• MeCP2 repressed transcriptional activity of PU.1 on a reporter construct with trimerized PU.1 binding sites [36].
• We further show that MECP2-expressing cells possess a functional p53 pathway and are still responsive to chemotherapeutic drugs [3].
• Brain-Specific Phosphorylation of MeCP2 Regulates Activity-Dependent Bdnf Transcription, Dendritic Growth, and Spine Maturation [37].
• The methyl-CpG-binding protein MeCP2 which promotes repressed chromatin structure is selectively detected in myofibroblasts of diseased liver. siRNA knockdown of MeCP2 elevated IkappaBalpha promoter activity, mRNA and protein expression in myofibroblasts [38].

Other interactions of MECP2

• Considering the similar phenotypes caused by mutations in MECP2 and CDKL5, it has been suggested that the two genes play a role in common pathogenic processes [39].
• Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3 [2].
• MECP2 encodes methyl-CpG-binding protein 2 that acts as a transcriptional repressor for methylated gene constructs but is surprisingly not required for maintaining imprinted gene expression [2].
• Although these histone deacetylase genes have been considered as good candidate genes for RTT our molecular analysis of these genes did not detect any mutations [40].
• The duplications in the four patients vary in size from 0.4 to 0.8 Mb and harbor several genes, which, for each duplication, include the MR-related L1CAM and MECP2 genes [7].

Analytical, diagnostic and therapeutic context of MECP2

• Long distance PCR coupled with long-read direct sequencing was employed to sequence the entire MECP2 gene coding region in all cases [41].
• Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location [41].
• METHODS: We screened by denaturing high-pressure liquid chromatography the entire coding region and flanking intronic sequences of the MECP2 gene in a cohort of 354 mentally retarded males found negative for an expansion across the FRAXA CGG repeat and in a family in which a boy and his sister were mentally retarded [21].
• Further evaluation of the therapeutic effects of these drugs in RTT animal models is needed before clinical trials can begin [42].
• These findings clearly call for a careful consideration of the pathogenicity of the MECP2 mutations identified in sporadic male cases before genetic counselling or prenatal diagnosis is proposed to the corresponding families [43].

References