Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease
Rett Syndrome (RTT) is a severe, rare, and progressive developmental disorder with patients displaying neurological regression and autism spectrum features. The affected individuals are primarily young females, and more than 95% of patients carry <i>de novo</i> mutation(s) in the Methyl-...
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MDPI AG
2021-01-01
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| Online Access: | https://www.mdpi.com/2218-273X/11/1/75 |
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| author | Shervin Pejhan Mojgan Rastegar |
| author_facet | Shervin Pejhan Mojgan Rastegar |
| author_sort | Shervin Pejhan |
| collection | DOAJ |
| description | Rett Syndrome (RTT) is a severe, rare, and progressive developmental disorder with patients displaying neurological regression and autism spectrum features. The affected individuals are primarily young females, and more than 95% of patients carry <i>de novo</i> mutation(s) in the Methyl-CpG-Binding Protein 2 (<i>MECP2)</i> gene. While the majority of RTT patients have <i>MECP2</i> mutations (classical RTT), a small fraction of the patients (atypical RTT) may carry genetic mutations in other genes such as the cyclin-dependent kinase-like 5 (<i>CDKL5)</i> and <i>FOXG1</i>. Due to the neurological basis of RTT symptoms, MeCP2 function was originally studied in nerve cells (neurons). However, later research highlighted its importance in other cell types of the brain including glia. In this regard, scientists benefitted from modeling the disease using many different cellular systems and transgenic mice with loss- or gain-of-function mutations. Additionally, limited research in human postmortem brain tissues provided invaluable findings in RTT pathobiology and disease mechanism. MeCP2 expression in the brain is tightly regulated, and its altered expression leads to abnormal brain function, implicating MeCP2 in some cases of autism spectrum disorders. In certain disease conditions, MeCP2 homeostasis control is impaired, the regulation of which in rodents involves a regulatory microRNA (<i>miR132</i>) and brain-derived neurotrophic factor (BDNF). Here, we will provide an overview of recent advances in understanding the underlying mechanism of disease in RTT and the associated genetic mutations in the <i>MECP2</i> gene along with the pathobiology of the disease, the role of the two most studied protein variants (MeCP2E1 and MeCP2E2 isoforms), and the regulatory mechanisms that control MeCP2 homeostasis network in the brain, including BDNF and <i>miR132</i>. |
| first_indexed | 2024-03-09T05:38:59Z |
| format | Article |
| id | doaj.art-6a8e16a883d0464d85f635bf342ad92f |
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| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T05:38:59Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-6a8e16a883d0464d85f635bf342ad92f2023-12-03T12:26:35ZengMDPI AGBiomolecules2218-273X2021-01-011117510.3390/biom11010075Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of DiseaseShervin Pejhan0Mojgan Rastegar1Regenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, CanadaRegenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, CanadaRett Syndrome (RTT) is a severe, rare, and progressive developmental disorder with patients displaying neurological regression and autism spectrum features. The affected individuals are primarily young females, and more than 95% of patients carry <i>de novo</i> mutation(s) in the Methyl-CpG-Binding Protein 2 (<i>MECP2)</i> gene. While the majority of RTT patients have <i>MECP2</i> mutations (classical RTT), a small fraction of the patients (atypical RTT) may carry genetic mutations in other genes such as the cyclin-dependent kinase-like 5 (<i>CDKL5)</i> and <i>FOXG1</i>. Due to the neurological basis of RTT symptoms, MeCP2 function was originally studied in nerve cells (neurons). However, later research highlighted its importance in other cell types of the brain including glia. In this regard, scientists benefitted from modeling the disease using many different cellular systems and transgenic mice with loss- or gain-of-function mutations. Additionally, limited research in human postmortem brain tissues provided invaluable findings in RTT pathobiology and disease mechanism. MeCP2 expression in the brain is tightly regulated, and its altered expression leads to abnormal brain function, implicating MeCP2 in some cases of autism spectrum disorders. In certain disease conditions, MeCP2 homeostasis control is impaired, the regulation of which in rodents involves a regulatory microRNA (<i>miR132</i>) and brain-derived neurotrophic factor (BDNF). Here, we will provide an overview of recent advances in understanding the underlying mechanism of disease in RTT and the associated genetic mutations in the <i>MECP2</i> gene along with the pathobiology of the disease, the role of the two most studied protein variants (MeCP2E1 and MeCP2E2 isoforms), and the regulatory mechanisms that control MeCP2 homeostasis network in the brain, including BDNF and <i>miR132</i>.https://www.mdpi.com/2218-273X/11/1/75epigeneticsDNA methylationMeCP2 isoformsMeCP2E1MeCP2E2BDNF |
| spellingShingle | Shervin Pejhan Mojgan Rastegar Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease Biomolecules epigenetics DNA methylation MeCP2 isoforms MeCP2E1 MeCP2E2 BDNF |
| title | Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease |
| title_full | Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease |
| title_fullStr | Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease |
| title_full_unstemmed | Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease |
| title_short | Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease |
| title_sort | role of dna methyl cpg binding protein mecp2 in rett syndrome pathobiology and mechanism of disease |
| topic | epigenetics DNA methylation MeCP2 isoforms MeCP2E1 MeCP2E2 BDNF |
| url | https://www.mdpi.com/2218-273X/11/1/75 |
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