Journal articles: 'Rett syndrome MeCP2'

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Liyanage, Vichithra R. B., and Mojgan Rastegar. "Rett Syndrome and MeCP2." NeuroMolecular Medicine 16, no. 2 (March 11, 2014): 231–64. http://dx.doi.org/10.1007/s12017-014-8295-9.

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Feldman, Danielle, Abhishek Banerjee, and Mriganka Sur. "Developmental Dynamics of Rett Syndrome." Neural Plasticity 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/6154080.

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Rett Syndrome was long considered to be simply a disorder of postnatal development, with phenotypes that manifest only late in development and into adulthood. A variety of recent evidence demonstrates that the phenotypes of Rett Syndrome are present at the earliest stages of brain development, including developmental stages that define neurogenesis, migration, and patterning in addition to stages of synaptic and circuit development and plasticity. These phenotypes arise from the pleotropic effects of MeCP2, which is expressed very early in neuronal progenitors and continues to be expressed into adulthood. The effects of MeCP2 are mediated by diverse signaling, transcriptional, and epigenetic mechanisms. Attempts to reverse the effects of Rett Syndrome need to take into account the developmental dynamics and temporal impact of MeCP2 loss.

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Bouzroud, Wafaa, Amal Tazzite, Sarah Berrada, Bouchaïb Gazzaz, and Hind Dehbi. "R306X Mutation in the MECP2 Gene Causes an Atypical Rett Syndrome in a Moroccan Patient: A Case Report." Clinical Pathology 15 (January 2022): 2632010X2211242. http://dx.doi.org/10.1177/2632010x221124269.

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Rett syndrome (RTT) is a rare X-linked syndrome that predominantly affects girls. It is characterized by a severe and progressive neurodevelopmental disorder with neurological regression and autism spectrum features. The Rett syndrome is associated with a broad phenotypic spectrum. It ranges from a classical Rett syndrome defined by well-established criteria to atypical cases with symptoms similar to other syndromes, such as Angelman syndrome. The first case of a Moroccan female child carrying a R306X mutation in the MECP2 (Methyl-CpG-Binding Protein 2) gene, with an unusual manifestation of Rett syndrome, is presented here. She showed autistic regression, behavioral stagnation, epilepsy, unmotivated laughter, and craniofacial dysmorphia. Whole exome sequencing revealed a nonsense mutation (R306X), resulting in a truncated, nonfunctional MECP2 protein. The overlapping phenotypic spectrums between Rett and Angelman syndromes have been described, and an interaction between the MECP2 gene and the UBE3A (Ubiquitin Protein Ligase E3A) gene pathways is possible but has not yet been proven. An extensive genetic analysis is highly recommended in atypical cases to ensure an accurate diagnosis and to improve patient management and genetic counseling.

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Tang, Xin, Julie Kim, Li Zhou, Eric Wengert, Lei Zhang, Zheng Wu, Cassiano Carromeu, et al. "KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome." Proceedings of the National Academy of Sciences 113, no. 3 (January 5, 2016): 751–56. http://dx.doi.org/10.1073/pnas.1524013113.

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Rett syndrome is a severe form of autism spectrum disorder, mainly caused by mutations of a single gene methyl CpG binding protein 2 (MeCP2) on the X chromosome. Patients with Rett syndrome exhibit a period of normal development followed by regression of brain function and the emergence of autistic behaviors. However, the mechanism behind the delayed onset of symptoms is largely unknown. Here we demonstrate that neuron-specific K+-Cl− cotransporter2 (KCC2) is a critical downstream gene target of MeCP2. We found that human neurons differentiated from induced pluripotent stem cells from patients with Rett syndrome showed a significant deficit in KCC2 expression and consequently a delayed GABA functional switch from excitation to inhibition. Interestingly, overexpression of KCC2 in MeCP2-deficient neurons rescued GABA functional deficits, suggesting an important role of KCC2 in Rett syndrome. We further identified that RE1-silencing transcriptional factor, REST, a neuronal gene repressor, mediates the MeCP2 regulation of KCC2. Because KCC2 is a slow onset molecule with expression level reaching maximum later in development, the functional deficit of KCC2 may offer an explanation for the delayed onset of Rett symptoms. Our studies suggest that restoring KCC2 function in Rett neurons may lead to a potential treatment for Rett syndrome.

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Collins, Bridget E., and Jeffrey L. Neul. "Rett Syndrome and MECP2 Duplication Syndrome: Disorders of MeCP2 Dosage." Neuropsychiatric Disease and Treatment Volume 18 (November 2022): 2813–35. http://dx.doi.org/10.2147/ndt.s371483.

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Saxena, Alka, Dave Tang, and Piero Carninci. "piRNAs Warrant Investigation in Rett Syndrome: An Omics Perspective." Disease Markers 33, no. 5 (2012): 261–75. http://dx.doi.org/10.1155/2012/396737.

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Mutations in the MECP2 gene are found in a large proportion of girls with Rett Syndrome. Despite extensive research, the principal role of MeCP2 protein remains elusive. Is MeCP2 a regulator of genes, acting in concert with co-activators and co-repressors, predominantly as an activator of target genes or is it a methyl CpG binding protein acting globally to change the chromatin state and to supress transcription from repeat elements? If MeCP2 has no specific targets in the genome, what causes the differential expression of specific genes in the Mecp2 knockout mouse brain? We discuss the discrepancies in current data and propose a hypothesis to reconcile some differences in the two viewpoints. Since transcripts from repeat elements contribute to piRNA biogenesis, we propose that piRNA levels may be higher in the absence of MeCP2 and that increased piRNA levels may contribute to the mis-regulation of some genes seen in the Mecp2 knockout mouse brain. We provide preliminary data showing an increase in piRNAs in the Mecp2 knockout mouse cerebellum. Our investigation suggests that global piRNA levels may be elevated in the Mecp2 knockout mouse cerebellum and strongly supports further investigation of piRNAs in Rett syndrome.

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Ehinger, Yann, Valerie Matagne, Laurent Villard, and Jean-Christophe Roux. "Rett syndrome from bench to bedside: recent advances." F1000Research 7 (March 26, 2018): 398. http://dx.doi.org/10.12688/f1000research.14056.1.

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Rett Syndrome is a severe neurological disorder mainly due to de novo mutations in the methyl-CpG-binding protein 2 gene (MECP2). Mecp2 is known to play a role in chromatin organization and transcriptional regulation. In this review, we report the latest advances on the molecular function of Mecp2 and the new animal and cellular models developed to better study Rett syndrome. Finally, we present the latest innovative therapeutic approaches, ranging from classical pharmacology to correct symptoms to more innovative approaches intended to cure the pathology.

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Ibrahim, Abdulkhaleg, Christophe Papin, Kareem Mohideen-Abdul, Stéphanie Le Gras, Isabelle Stoll, Christian Bronner, Stefan Dimitrov, Bruno P. Klaholz, and Ali Hamiche. "MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion." Science 372, no. 6549 (June 24, 2021): eabd5581. http://dx.doi.org/10.1126/science.abd5581.

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The Rett syndrome protein MeCP2 was described as a methyl-CpG-binding protein, but its exact function remains unknown. Here we show that mouse MeCP2 is a microsatellite binding protein that specifically recognizes hydroxymethylated CA repeats. Depletion of MeCP2 alters chromatin organization of CA repeats and lamina-associated domains and results in nucleosome accumulation on CA repeats and genome-wide transcriptional dysregulation. The structure of MeCP2 in complex with a hydroxymethylated CA repeat reveals a characteristic DNA shape, with considerably modified geometry at the 5-hydroxymethylcytosine, which is recognized specifically by Arg133, a key residue whose mutation causes Rett syndrome. Our work identifies MeCP2 as a microsatellite DNA binding protein that targets the 5hmC-modified CA-rich strand and maintains genome regions nucleosome-free, suggesting a role for MeCP2 dysfunction in Rett syndrome.

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Kyle, Stephanie M., Neeti Vashi, and Monica J. Justice. "Rett syndrome: a neurological disorder with metabolic components." Open Biology 8, no. 2 (February 2018): 170216. http://dx.doi.org/10.1098/rsob.170216.

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Rett syndrome (RTT) is a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 ( MECP2 ), a ubiquitously expressed transcriptional regulator. Despite remarkable scientific progress since its discovery, the mechanism by which MECP2 mutations cause RTT symptoms is largely unknown. Consequently, treatment options for patients are currently limited and centred on symptom relief. Thought to be an entirely neurological disorder, RTT research has focused on the role of MECP2 in the central nervous system. However, the variety of phenotypes identified in Mecp2 mutant mouse models and RTT patients implicate important roles for MeCP2 in peripheral systems. Here, we review the history of RTT, highlighting breakthroughs in the field that have led us to present day. We explore the current evidence supporting metabolic dysfunction as a component of RTT, presenting recent studies that have revealed perturbed lipid metabolism in the brain and peripheral tissues of mouse models and patients. Such findings may have an impact on the quality of life of RTT patients as both dietary and drug intervention can alter lipid metabolism. Ultimately, we conclude that a thorough knowledge of MeCP2's varied functional targets in the brain and body will be required to treat this complex syndrome.

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Pecorelli, Alessandra, Valeria Cordone, Maria Lucia Schiavone, Carla Caffarelli, Carlo Cervellati, Gaetana Cerbone, Stefano Gonnelli, Joussef Hayek, and Giuseppe Valacchi. "Altered Bone Status in Rett Syndrome." Life 11, no. 6 (June 3, 2021): 521. http://dx.doi.org/10.3390/life11060521.

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Rett syndrome (RTT) is a monogenic neurodevelopmental disorder primarily caused by mutations in X-linked MECP2 gene, encoding for methyl-CpG binding protein 2 (MeCP2), a multifaceted modulator of gene expression and chromatin organization. Based on the type of mutation, RTT patients exhibit a broad spectrum of clinical phenotypes with various degrees of severity. In addition, as a complex multisystem disease, RTT shows several clinical manifestations ranging from neurological to non-neurological symptoms. The most common non-neurological comorbidities include, among others, orthopedic complications, mainly scoliosis but also early osteopenia/osteoporosis and a high frequency of fractures. A characteristic low bone mineral density dependent on a slow rate of bone formation due to dysfunctional osteoblast activity rather than an increase in bone resorption is at the root of these complications. Evidence from human and animal studies supports the idea that MECP2 mutation could be associated with altered epigenetic regulation of bone-related factors and signaling pathways, including SFRP4/WNT/β-catenin axis and RANKL/RANK/OPG system. More research is needed to better understand the role of MeCP2 in bone homeostasis. Indeed, uncovering the molecular mechanisms underlying RTT bone problems could reveal new potential pharmacological targets for the treatment of these complications that adversely affect the quality of life of RTT patients for whom the only therapeutic approaches currently available include bisphosphonates, dietary supplements, and physical activity.

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Marano, Domenico, Salvatore Fioriniello, Maurizio D’Esposito, and Floriana Della Ragione. "Transcriptomic and Epigenomic Landscape in Rett Syndrome." Biomolecules 11, no. 7 (June 30, 2021): 967. http://dx.doi.org/10.3390/biom11070967.

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Rett syndrome (RTT) is an extremely invalidating, cureless, developmental disorder, and it is considered one of the leading causes of intellectual disability in female individuals. The vast majority of RTT cases are caused by de novo mutations in the X-linked Methyl-CpG binding protein 2 (MECP2) gene, which encodes a multifunctional reader of methylated DNA. MeCP2 is a master epigenetic modulator of gene expression, with a role in the organization of global chromatin architecture. Based on its interaction with multiple molecular partners and the diverse epigenetic scenario, MeCP2 triggers several downstream mechanisms, also influencing the epigenetic context, and thus leading to transcriptional activation or repression. In this frame, it is conceivable that defects in such a multifaceted factor as MeCP2 lead to large-scale alterations of the epigenome, ranging from an unbalanced deposition of epigenetic modifications to a transcriptional alteration of both protein-coding and non-coding genes, with critical consequences on multiple downstream biological processes. In this review, we provide an overview of the current knowledge concerning the transcriptomic and epigenomic alterations found in RTT patients and animal models.

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Millichap, J. Gordon. "MECP2 Mutations and Rett Syndrome Phenotypes." Pediatric Neurology Briefs 14, no. 5 (May 1, 2000): 39. http://dx.doi.org/10.15844/pedneurbriefs-14-5-10.

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Samaco, R. C., and J. L. Neul. "Complexities of Rett Syndrome and MeCP2." Journal of Neuroscience 31, no. 22 (June 1, 2011): 7951–59. http://dx.doi.org/10.1523/jneurosci.0169-11.2011.

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Webb, T. "Rett syndrome and the MECP2 gene." Journal of Medical Genetics 38, no. 4 (April 1, 2001): 217–23. http://dx.doi.org/10.1136/jmg.38.4.217.

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Lee, Kenneth. "Mouse Mecp2 knockouts and Rett syndrome." Genome Biology 2 (2001): spotlight—20010309–02. http://dx.doi.org/10.1186/gb-spotlight-20010309-02.

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Gauthier, Julie, Giovana de Amorim, Gevork N. Mnatzakanian, Carol Saunders, John B. Vincent, Sylvie Toupin, David Kauffman, et al. "Clinical Stringency Greatly Improves Mutation Detection in Rett Syndrome." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 32, no. 3 (August 2005): 321–26. http://dx.doi.org/10.1017/s0317167100004200.

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ABSTRACT:Background:Rett syndrome (RTT) is a severe neurodevelopmental disorder of girls, caused by mutations in the X-linked MECP2 gene. Worldwide recognition of the RTT clinical phenotype in the early 1980's allowed many cases to be diagnosed, and established RTT as one of the most common mental retardation syndromes in females. The years since then led to a refinement of the phenotype and the recent elaboration of Revised Diagnostic Criteria (RDC). Here, we study the impact of the presence versus the absence of the use of diagnostic criteria from the RDC to make a diagnosis of RTT on MECP2 mutation detection in Canadian patients diagnosed and suspected of having RTT.Methods:Using dHPLC followed by sequencing in all exons of the MECP2 gene, we compared mutation detection in a historic cohort of 35 patients diagnosed with RTT without the use of specific diagnostic criteria to a separate more recent group of 101 patients included on the basis of strict fulfillment of the RDC.Results:The MECP2 mutation detection rate was much higher in subjects diagnosed using a strict adherence to the RDC (20% vs. 72%).Conclusions:These results suggest that clinical diagnostic procedures significantly influence the rate of mutation detection in RTT, and more generally emphasize the importance of diagnostic tools in the assessment of neurobehavioral syndromes.

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Cronk, James, Noel Derecki, Aleksandra Djukic, and Jonathan Kipnis. "Immunologic dysfunction underlies pathology in a mouse model of Rett syndrome. (111.52)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 111.52. http://dx.doi.org/10.4049/jimmunol.188.supp.111.52.

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Abstract Rett syndrome is a devastating autism spectrum disorder, characterized by tremors, breathing dysregulation, impaired locomotion, and mental retardation. Most cases are caused by mutation of the X-linked gene, MECP2, which encodes a methyl-CpG-binding protein. Although MECP2 is expressed in many cell types, pathology has been generally attributed to neuronal dysfunction. However, we recently showed striking arrest of disease in the Mecp2-null mouse model of Rett by manipulation of the immune system. LysmCre-directed wild type MECP2 expression in myeloid cells of Mecp2-null mice and bone-marrow transplantation from wild type into Mecp2-null mice both markedly improved several disease sequelae. When peripheral myeloid cells from Mecp2-null mice were examined, they were significantly impaired in cytokine production (TNF and IL-10) and growth factors (IGF-1) after stimulation, and in phagocytosis. Moreover, peripheral organs from Mecp2-mutant mice showed significantly increased levels of monocytes and granulocytes, as well as a striking skew towards a naïve (CD62LHigh/CD44low) phenotype of T cells. In addition, spleens and livers of Mecp2-mutant mice are significantly smaller than those from wild type. Importantly, these findings correlated with data from human patients, who displayed similar hematologic changes. These data suggest that loss of Mecp2 may lead to immunologic dysfunction, which could underlie pathologies seen in Rett syndrome.

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Cappuccio, Donti, Pinelli, Bernardo, Bravaccio, Elsea, and Brunetti-Pierri. "Sphingolipid Metabolism Perturbations in Rett Syndrome." Metabolites 9, no. 10 (October 10, 2019): 221. http://dx.doi.org/10.3390/metabo9100221.

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Rett syndrome is a severe neurodevelopmental disorder affecting mostly females and is caused by loss-of-function mutations in the MECP2 gene that encoded the methyl-CpG-binding protein 2. The pathogenetic mechanisms of Rett syndrome are not completely understood and metabolic derangements are emerging as features of Rett syndrome. We performed a semi-quantitative tandem mass spectrometry-based analysis that measured over 900 metabolites on blood samples from 14 female subjects with Rett syndrome carrying MECP2 mutations. The metabolic profiling revealed alterations in lipids, mostly involved in sphingolipid metabolism, and sphinganine/sphingosine, that are known to have a neurotrophic role. Further investigations are required to understand the mechanisms underlying such perturbations and their significance in the disease pathogenesis. Nevertheless, these metabolites are attractive for studies on the disease pathogenesis and as potential disease biomarkers.

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Dad, Rubina, Humaira Aziz Sawal, Arsalan Ahmad, Muhammad Ikram Ullah, and Muhammad Jawad Hassan. "Rett Syndrome without MECP2 Mutation in a Pakistani Girl." Life and Science 1, no. 2 (April 14, 2020): 3. http://dx.doi.org/10.37185/lns.1.1.77.

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Rett syndrome is a rare inherited neurodegenerative disease which mostly affects females but has a lethal impact on males. Rett syndrome is mostly caused by mutations of Methyl CpG binding protein-2 (MECP2) gene located on chromosome Xq28. A 7-year girl from a consanguineous Pakistani family presented with history of abnormal social behavior, tonic colonic seizures, limb'sataxia, intellectual disability, growth retardation and speech abnormalities. Physical and neurological examinations established likely clinical features of Rett syndrome with abnormal electroencephalogram (EEG). Genetic testing of MECP2 gene did not identify any functional nucleotide variation indicating the involvement of another gene mutation in this patient.A consanguineous case of Rett syndrome did not carry the mutation of MECP2 gene. Due to heterogeneity of the phenotype, it is proposed that there might be involvement of another locus for this disease. In future, targeted next generation sequence can be helpful to identify the causative mutation in this patient.

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Bird, Adrian. "The methyl-CpG-binding protein MeCP2 and neurological disease." Biochemical Society Transactions 36, no. 4 (July 22, 2008): 575–83. http://dx.doi.org/10.1042/bst0360575.

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The methyl-CpG-binding protein MeCP2 was discovered over 15 years ago as part of a search for proteins that selectively bind methylated DNA. It is a nuclear protein that is largely chromatin-bound and has a strong preference for binding to methylated DNA sequences in vivo. Evidence from model systems shows that MeCP2 can recruit the Sin3a co-repressor complex to promoters leading to transcriptional repression, therefore suggesting that MeCP2 can interpret the DNA methylation signal to bring about gene silencing. Mutations in the human MECP2 gene cause the autism spectrum disorder Rett Syndrome. MeCP2 is most highly expressed in neurons, and mice lacking this protein show symptoms that strikingly parallel those of Rett patients. Surprisingly, these symptoms are efficiently reversed by delayed activation of a ‘stopped’ Mecp2 gene, raising hopes that human Rett syndrome may also be reversible. Future studies of MeCP2 promise to shed light upon brain function, neurological disease and the biology of DNA methylation.

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Gadalla, Kamal K. E., Mark E. S. Bailey, and Stuart R. Cobb. "MeCP2 and Rett syndrome: reversibility and potential avenues for therapy." Biochemical Journal 439, no. 1 (September 14, 2011): 1–14. http://dx.doi.org/10.1042/bj20110648.

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Mutations in the X-linked gene MECP2 (methyl CpG-binding protein 2) are the primary cause of the neurodevelopmental disorder RTT (Rett syndrome), and are also implicated in other neurological conditions. The expression product of this gene, MeCP2, is a widely expressed nuclear protein, especially abundant in mature neurons of the CNS (central nervous system). The major recognized consequences of MECP2 mutation occur in the CNS, but there is growing awareness of peripheral effects contributing to the full RTT phenotype. MeCP2 is classically considered to act as a DNA methylation-dependent transcriptional repressor, but may have additional roles in regulating gene expression and chromatin structure. Knocking out Mecp2 function in mice recapitulates many of the overt neurological features seen in RTT patients, and the characteristic postnatally delayed onset of symptoms is accompanied by aberrant neuronal morphology and deficits in synaptic physiology. Evidence that reactivation of endogenous Mecp2 in mutant mice, even at adult stages, can reverse aspects of RTT-like pathology and result in apparently functionally mature neurons has provided renewed hope for patients, but has also provoked discussion about traditional boundaries between neurodevelopmental disorders and those involving dysfunction at later stages. In the present paper we review the neurobiology of MeCP2 and consider the various genetic (including gene therapy), pharmacological and environmental interventions that have been, and could be, developed to attempt phenotypic rescue in RTT. Such approaches are already providing valuable insights into the potential tractability of RTT and related conditions, and are useful pointers for the development of future therapeutic strategies.

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Lima, Fernanda T. de, Decio Brunoni, José Salomão Schwartzman, Maria Cristina Pozzi, Fernando Kok, Yara Juliano, and Lygia da Veiga Pereira. "Genotype-phenotype correlation in Brazillian Rett syndrome patients." Arquivos de Neuro-Psiquiatria 67, no. 3a (September 2009): 577–84. http://dx.doi.org/10.1590/s0004-282x2009000400001.

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BACKGROUND: Rett syndrome (RS) is a severe neurodevelopmental X-linked dominant disorder caused by mutations in the MECP2 gene. PURPOSE: To search for point mutations on the MECP2 gene and to establish a correlation between the main point mutations found and the phenotype. METHOD: Clinical evaluation of 105 patients, following a standard protocol. Detection of point mutations on the MECP2 gene was performed on peripheral blood DNA by sequencing the coding region of the gene. RESULTS: Classical RS was seen in 68% of the patients. Pathogenic point mutations were found in 64.1% of all patients and in 70.42% of those with the classical phenotype. Four new sequence variations were found, and their nature suggests patogenicity. Genotype-phenotype correlations were performed. CONCLUSION: Detailed clinical descriptions and identification of the underlying genetic alterations of this Brazilian RS population add to our knowledge of genotype/phenotype correlations, guiding the implementation of mutation searching programs.

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Kriaucionis, Skirmantas, Andrew Paterson, John Curtis, Jacky Guy, Nikki MacLeod, and Adrian Bird. "Gene Expression Analysis Exposes Mitochondrial Abnormalities in a Mouse Model of Rett Syndrome." Molecular and Cellular Biology 26, no. 13 (July 1, 2006): 5033–42. http://dx.doi.org/10.1128/mcb.01665-05.

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ABSTRACT Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the X-linked MECP2 gene, which encodes a methyl-CpG binding transcriptional repressor. Using the Mecp2-null mouse (an animal model for RTT) and differential display, we found that mice with neurological symptoms overexpress the nuclear gene for ubiquinol-cytochrome c reductase core protein 1 (Uqcrc1). Chromatin immunoprecipitation demonstrated that MeCP2 interacts with the Uqcrc1 promoter. Uqcrc1 encodes a subunit of mitochondrial respiratory complex III, and isolated mitochondria from the Mecp2-null brain showed elevated respiration rates associated with respiratory complex III and an overall reduction in coupling. A causal link between Uqcrc1 gene overexpression and enhanced complex III activity was established in neuroblastoma cells. Our findings raise the possibility that mitochondrial dysfunction contributes to pathology of the Mecp2-null mouse and may contribute to the long-known resemblance between Rett syndrome and certain mitochondrial disorders.

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Stachon, Andrea, Francisco Baptista Assumpção Jr, and Salmo Raskin. "Rett syndrome: clinical and molecular characterization of two Brazilian patients." Arquivos de Neuro-Psiquiatria 65, no. 1 (March 2007): 36–40. http://dx.doi.org/10.1590/s0004-282x2007000100009.

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BACKGROUND: Rett syndrome (RS) is recognized as a pan-ethnic condition. Since the identification of mutations in the MECP2 gene, more patients have been diagnosed, and a broad spectrum of phenotypes has been reported. There is a lack of phenotype-genotype studies. OBJECTIVE: To describe two cases of Brazilian patients with identified MECP2 mutations. METHOD: We present two female Brazilian patients with RS. RESULTS: Both patients presented with regression at 2-3 years of age, when stereotypic hand movements, social withdrawal and postnatal deceleration of head growth rate were observed. Both patients presented verbal communication impairment. Case 1 had loss of purposeful hand movements, and severe seizure episodes. Case 2 had milder impairment of purposeful hand movements, and no seizures. They had different mutations, D97Y and R294X, found in exons 3 and 4 of MECP2 gene, respectively. CONCLUSION: Testing for MECP2 mutations is important to confirm diagnosis and to establish genotype/phenotype correlations, and improve genetic counseling.

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Djarmati, A., V. Dobričić, M. Kecmanović, P. Marsh, J. Jančić-Stefanović, C. Klein, M. Djurić, and S. Romac. "MECP2 mutations in Serbian Rett syndrome patients." Acta Neurologica Scandinavica 116, no. 6 (December 2007): 413–19. http://dx.doi.org/10.1111/j.1600-0404.2007.00893.x.

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Sung Jae Lee, Stephen, Mimi Wan, and Uta Francke. "Spectrum of MECP2 mutations in Rett syndrome." Brain and Development 23 (December 2001): S138—S143. http://dx.doi.org/10.1016/s0387-7604(01)00339-4.

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Xiang, F., Y. Stenbom, and M. Anvret. "MECP2 mutations in Swedish Rett syndrome clusters." Clinical Genetics 61, no. 5 (May 2002): 384–85. http://dx.doi.org/10.1034/j.1399-0004.2002.610512.x.

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Bienvenu, Thierry, Laurent Villard, Nicolas De Roux, Violaine Bourdon, Michel Fontes, Cherif Beldjord, Marc Tardieu, Philippe Jonveaux, and Jamel Chelly. "Spectrum of MECP2 Mutations in Rett Syndrome." Genetic Testing 6, no. 1 (March 2002): 1–6. http://dx.doi.org/10.1089/109065702760093843.

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Fischer, Marc, Julia Reuter, Florian J. Gerich, Belinda Hildebrandt, Sonja Hägele, Dörthe Katschinski, and Michael Müller. "Enhanced Hypoxia Susceptibility in Hippocampal Slices From a Mouse Model of Rett Syndrome." Journal of Neurophysiology 101, no. 2 (February 2009): 1016–32. http://dx.doi.org/10.1152/jn.91124.2008.

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Rett syndrome is a neurodevelopmental disorder caused by mutations in the X-chromosomal MECP2 gene encoding for the transcriptional regulator methyl CpG binding protein 2 (MeCP2). Rett patients suffer from episodic respiratory irregularities and reduced arterial oxygen levels. To elucidate whether such intermittent hypoxic episodes induce adaptation/preconditioning of the hypoxia-vulnerable hippocampal network, we analyzed its responses to severe hypoxia in adult Rett mice. The occurrence of hypoxia-induced spreading depression (HSD)—an experimental model for ischemic stroke—was hastened in Mecp2− /y males. The extracellular K+ rise during HSD was attenuated in Mecp2− /y males and the input resistance of CA1 pyramidal neurons decreased less before HSD onset. CA1 pyramidal neurons were smaller and more densely packed, but the cell swelling during HSD was unaffected. The intrinsic optical signal and the propagation of HSD were similar among the different genotypes. Basal synaptic function was intact, but Mecp2− /y males showed reduced paired-pulse facilitation and higher field potential/fiber volley ratios, but no increased seizure susceptibility. Synaptic failure during hypoxia was complete in all genotypes and the final degree of posthypoxic synaptic recovery indistinguishable. Cellular ATP content was normal in Mecp2− /y males, but their hematocrit was increased as was HIF-1α expression throughout the brain. This is the first study showing that in Rett syndrome, the susceptibility of telencephalic neuronal networks to hypoxia is increased; the underlying molecular mechanisms apparently involve disturbed K+ channel function. Such an increase in hypoxia susceptibility may potentially contribute to the vulnerability of male Rett patients who are either not viable or severely disabled.

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Zachariah, Robby Mathew, and Mojgan Rastegar. "Linking Epigenetics to Human Disease and Rett Syndrome: The Emerging Novel and Challenging Concepts in MeCP2 Research." Neural Plasticity 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/415825.

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Epigenetics refer to inheritable changes beyond DNA sequence that control cell identity and morphology. Epigenetics play key roles in development and cell fate commitments and highly impact the etiology of many human diseases. A well-known link between epigenetics and human disease is the X-linkedMECP2gene, mutations in which lead to the neurological disorder, Rett Syndrome. Despite the fact that MeCP2 was discovered about 20 years ago, our current knowledge about its molecular function is not comprehensive. While MeCP2 was originally found to bind methylated DNA and interact with repressor complexes to inhibit and silence its genomic targets, recent studies have challenged this idea. Indeed, depending on its interacting protein partners and target genes, MeCP2 can act either as an activator or as a repressor. Furthermore, it is becoming evident that although Rett Syndrome is a progressive and postnatal neurological disorder, the consequences of MeCP2 deficiencies initiate much earlier and before birth. To comprehend the novel and challenging concepts in MeCP2 research and to design effective therapeutic strategies for Rett Syndrome, a targeted collaborative effort from scientists in multiple research areas to clinicians is required.

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Johnson, Rebecca A., Maxine Lam, Antonio M. Punzo, Hongda Li, Benjamin R. Lin, Keqiang Ye, Gordon S. Mitchell, and Qiang Chang. "7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome." Journal of Applied Physiology 112, no. 5 (March 1, 2012): 704–10. http://dx.doi.org/10.1152/japplphysiol.01361.2011.

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Rett syndrome (RTT), caused by mutations in the methyl-CpG binding protein 2 gene ( MECP2), is a debilitating autism spectrum developmental disorder predominantly affecting females. Mecp2 mutant mice have reduced levels of brain-derived neurotrophic factor (BDNF) in the brain; conditional deletion and overexpression of BDNF in the brain accelerates and slows, respectively, disease progression in Mecp2 mutant mice. Thus we tested the hypothesis that 7,8-dihydroxyflavone (7,8-DHF), a small molecule reported to activate the high affinity BDNF receptor (TrkB) in the CNS, would attenuate disease progression in Mecp2 mutant mice. Following weaning, 7,8-DHF was administered in drinking water throughout life. Treated mutant mice lived significantly longer compared with untreated mutant littermates (80 ± 4 and 66 ± 2 days, respectively). 7,8-DHF delayed body weight loss, increased neuronal nuclei size and enhanced voluntary locomotor (running wheel) distance in Mecp2 mutant mice. In addition, administration of 7,8-DHF partially improved breathing pattern irregularities and returned tidal volumes to near wild-type levels. Thus although the specific mechanisms are not completely known, 7,8-DHF appears to reduce disease symptoms in Mecp2 mutant mice and may have potential as a therapeutic treatment for RTT patients.

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Merritt, Jonathan K., Bridget E. Collins, Kirsty R. Erickson, Hongwei Dong, and Jeffrey L. Neul. "Pharmacological read-through of R294X Mecp2 in a novel mouse model of Rett syndrome." Human Molecular Genetics 29, no. 15 (May 29, 2020): 2461–70. http://dx.doi.org/10.1093/hmg/ddaa102.

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Abstract Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in Methyl-CpG-binding Protein 2 (MECP2). More than 35% of affected individuals have nonsense mutations in MECP2. For these individuals, nonsense suppression has been suggested as a possible therapeutic approach. To assess the viability of this strategy, we created and characterized a mouse model with the common p.R294X mutation introduced into the endogenous Mecp2 locus (Mecp2R294X). Mecp2R294X mice exhibit phenotypic abnormalities similar to those seen in complete null mouse models; however, these occur at a later time point consistent with the reduced phenotypic severity seen in affected individuals containing this specific mutation. The delayed onset of severe phenotypes is likely due to the presence of truncated MeCP2 in Mecp2R294X mice. Supplying the MECP2 transgene in Mecp2R294X mice rescued phenotypic abnormalities including early death and demonstrated that the presence of truncated MeCP2 in these mice does not interfere with wild-type MeCP2. In vitro treatment of a cell line derived from Mecp2R294X mice with the nonsense suppression agent G418 resulted in full-length MeCP2 protein production, demonstrating feasibility of this therapeutic approach. Intraperitoneal administration of G418 in Mecp2R294X mice was sufficient to elicit full-length MeCP2 protein expression in peripheral tissues. Finally, intracranial ventricular injection of G418 in Mecp2R294X mice induced expression of full-length MeCP2 protein in the mouse brain. These experiments demonstrate that translational read-through drugs are able to suppress the Mecp2 p.R294X mutation in vivo and provide a proof of concept for future preclinical studies of nonsense suppression agents in RTT.

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Cobb, Stuart, Jacky Guy, and Adrian Bird. "Reversibility of functional deficits in experimental models of Rett syndrome." Biochemical Society Transactions 38, no. 2 (March 22, 2010): 498–506. http://dx.doi.org/10.1042/bst0380498.

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Mutations in the X-linked MECP2 gene are the primary cause of the severe autism spectrum disorder RTT (Rett syndrome). Deletion of Mecp2 in mice recapitulates many of the overt neurological features seen in humans, and the delayed onset of symptoms is accompanied by deficits in neuronal morphology and synaptic physiology. Recent evidence suggests that reactivation of endogenous Mecp2 in young and adult mice can reverse aspects of RTT-like pathology. In the current perspective, we discuss these findings as well as other genetic, pharmacological and environmental interventions that attempt phenotypic rescue in RTT. We believe these studies provide valuable insights into the tractability of RTT and related conditions and are useful pointers for the development of future therapeutic strategies.

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Schmidt, Annika, Hui Zhang, and M. Cristina Cardoso. "MeCP2 and Chromatin Compartmentalization." Cells 9, no. 4 (April 3, 2020): 878. http://dx.doi.org/10.3390/cells9040878.

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Methyl-CpG binding protein 2 (MeCP2) is a multifunctional epigenetic reader playing a role in transcriptional regulation and chromatin structure, which was linked to Rett syndrome in humans. Here, we focus on its isoforms and functional domains, interactions, modifications and mutations found in Rett patients. Finally, we address how these properties regulate and mediate the ability of MeCP2 to orchestrate chromatin compartmentalization and higher order genome architecture.

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Dziwota, Ewelina, Urszula Fałkowska, Katarzyna Adamczyk, Dorota Adamczyk, Alena Stefańska, Justyna Pawęzka, and Marcin Olajossy. "Silent angels the genetic and clinical aspects of Rett syndrome." Current Problems of Psychiatry 17, no. 4 (December 1, 2016): 282–96. http://dx.doi.org/10.1515/cpp-2016-0028.

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AbstractRett syndrome is a neurodevelopmental genetic disorder and, because of some behavioral characteristics, individuals affected by the disease are known as silent angels. Girls with Rett syndrome perform stereotyped movements, they have learning difficulties, their reaction time is prolonged, and they seem alienated in the environment. These children require constant pediatric, neurological and orthopedic care. In the treatment of Rett syndrome physical therapy, music therapy, hydrotherapy, hippotherapy, behavioral methods, speech therapy and diet, are also used. In turn, psychological therapy of the syndrome is based on the sensory integration method, using two or more senses simultaneously. In 80% of cases, the syndrome is related to mutations of the MECP2 gene, located on chromosome X. The pathogenesis of Rett syndrome is caused by the occurrence of a non-functional MeCP2 protein, which is a transcription factor of many genes, i.e. Bdnf, mef2c, Sgk1, Uqcrc1. Abnormal expression of these genes reveals a characteristic disease phenotype. Clinical symptoms relate mainly to the nervous, respiratory, skeletal and gastrointestinal systems. Currently causal treatment is not possible. However, researchers are developing methods by which, perhaps in the near future, it will be possible to eliminate the mutations in the MECP2 gene, and this will give a chance to the patient for normal functioning.The paper presents the etiology and pathogenesis of the disease, genetic, clinical, pharmacological aspects and other forms of Rett syndrome treatment.

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Damen, Daniela, and Rolf Heumann. "MeCP2 phosphorylation in the brain: from transcription to behavior." Biological Chemistry 394, no. 12 (December 1, 2013): 1595–605. http://dx.doi.org/10.1515/hsz-2013-0193.

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Abstract Methyl-CpG binding protein 2 (MeCP2), a nuclear protein highly expressed in neurons, was identified because of its ability to bind methylated DNA. In association with the transcriptional corepressor proteins Sin3a and histone deacetylases, it represses gene transcription. However, it has since become clear that MeCP2 is a multifunctional protein involved not only in transcriptional silencing but also in transcriptional activation, chromatin remodeling, and RNA splicing. Especially, its involvement in the X-linked neurologic disorder Rett syndrome emphasizes the importance of MeCP2 for normal development and maturation of the central nervous system. A number of animal models with complete or partial lack of MeCP2 functions have been generated to correlate the clinical phenotype of Rett syndrome, and studies involving different mutations of MeCP2 have shown similar effects. Animal model studies have further demonstrated that even the loss of a specific phosphorylation site of MeCP2 (S80, S421, and S424) disturbs normal maturation of the mammalian brain. This review covers recent findings regarding MeCP2 functions and its regulation by posttranslational modification, particularly MeCP2 phosphorylation and its effects on mammalian brain maturation, learning, and plasticity.

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Bhattacherjee, Aritra, Ying Mu, Michelle K. Winter, Jennifer R. Knapp, Linda S. Eggimann, Sumedha S. Gunewardena, Kazuto Kobayashi, Shigeki Kato, Dora Krizsan-Agbas, and Peter G. Smith. "Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome." Proceedings of the National Academy of Sciences 114, no. 33 (July 31, 2017): E6952—E6961. http://dx.doi.org/10.1073/pnas.1618210114.

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Children with Rett syndrome show abnormal cutaneous sensitivity. The precise nature of sensory abnormalities and underlying molecular mechanisms remain largely unknown. Rats with methyl-CpG binding protein 2 (MeCP2) mutation, characteristic of Rett syndrome, show hypersensitivity to pressure and cold, but hyposensitivity to heat. They also show cutaneous hyperinnervation by nonpeptidergic sensory axons, which include subpopulations encoding noxious mechanical and cold stimuli, whereas peptidergic thermosensory innervation is reduced. MeCP2 knockdown confined to dorsal root ganglion sensory neurons replicated this phenotype in vivo, and cultured MeCP2-deficient ganglion neurons showed augmented axonogenesis. Transcriptome analysis revealed dysregulation of genes associated with cytoskeletal dynamics, particularly those controlling actin polymerization and focal-adhesion formation necessary for axon growth and mechanosensory transduction. Down-regulation of these genes by topoisomerase inhibition prevented abnormal axon sprouting. We identified eight key affected genes controlling actin signaling and adhesion formation, including members of the Arhgap, Tiam, and cadherin families. Simultaneous virally mediated knockdown of these genes in Rett rats prevented sensory hyperinnervation and reversed mechanical hypersensitivity, indicating a causal role in abnormal outgrowth and sensitivity. Thus, MeCP2 regulates ganglion neuronal genes controlling cytoskeletal dynamics, which in turn determines axon outgrowth and mechanosensory function and may contribute to altered pain sensitivity in Rett syndrome.

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Duncan Armstrong, Dawna, Kimiko Deguchi, and Bobbie Antallfy. "Survey of MeCP2 in the Rett Syndrome and the Non—Rett Syndrome Brain." Journal of Child Neurology 18, no. 10 (October 2003): 683–87. http://dx.doi.org/10.1177/08830738030180100601.

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Kucukkal, Tugba G., and Rijul U. Amin. "Computational and structural studies of MeCP2 and associated mutants." Journal of Theoretical and Computational Chemistry 19, no. 06 (July 8, 2020): 2041001. http://dx.doi.org/10.1142/s0219633620410011.

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Rett Syndrome is a rare genetic disorder exclusively seen in girls. Approximately 95% of RTT cases is caused by mutations in the MeCP2 gene which codes for Methyl-CpG-binding protein 2 (MeCP2). In this review, first, a brief introductory review of Rett Syndrome, MeCP2 protein structure and function, mutation types and frequencies, and phenotype–genotype relationships were provided. After that, the current knowledge on the wild-type and mutant MeCP2 protein structure and dynamics as well as its binding to DNA is reviewed. The review particularly focuses on computational (such as molecular dynamics) and experimental (such as electrophoretic mobility shift assays) studies on the MeCP2 binding to different types of DNA as well as the computational and experimental (such as circular dichroism) studies on the stability changes upon mutations. In the end, a brief opinion on future outlook for further computational studies is provided.

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Haase, Florencia, Brian S. Gloss, Patrick P. L. Tam, and Wendy A. Gold. "WGCNA Identifies Translational and Proteasome-Ubiquitin Dysfunction in Rett Syndrome." International Journal of Molecular Sciences 22, no. 18 (September 15, 2021): 9954. http://dx.doi.org/10.3390/ijms22189954.

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Rett Syndrome (RTT) is an X linked neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, resulting in severe cognitive and physical disabilities. Despite an apparent normal prenatal and postnatal development period, symptoms usually present around 6 to 18 months of age. Little is known about the consequences of MeCP2 deficiency at a molecular and cellular level before the onset of symptoms in neural cells, and subtle changes at this highly sensitive developmental stage may begin earlier than symptomatic manifestation. Recent transcriptomic studies of patient induced pluripotent stem cells (iPSC)-differentiated neurons and brain organoids harbouring pathogenic mutations in MECP2, have unravelled new insights into the cellular and molecular changes caused by these mutations. Here we interrogated transcriptomic modifications in RTT patients using publicly available RNA-sequencing datasets of patient iPSCs harbouring pathogenic mutations and healthy control iPSCs by Weighted Gene Correlation Network Analysis (WGCNA). Preservation analysis identified core gene pathways involved in translation, ribosomal function, and ubiquitination perturbed in some MECP2 mutant iPSC lines. Furthermore, differential gene expression of the parental fibroblasts and iPSC-derived neurons revealed alterations in genes in the ubiquitination pathway and neurotransmission in fibroblasts and differentiated neurons respectively. These findings might suggest that global translational dysregulation and proteasome ubiquitin function in Rett syndrome begins in progenitor cells prior to lineage commitment and differentiation into neural cells.

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Rangasamy, Sampathkumar, Shannon Olfers, Brittany Gerald, Alex Hilbert, Sean Svejda, and Vinodh Narayanan. "Reduced neuronal size and mTOR pathway activity in the Mecp2 A140V Rett syndrome mouse model." F1000Research 5 (September 8, 2016): 2269. http://dx.doi.org/10.12688/f1000research.8156.1.

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Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation in the X-linked MECP2 gene, encoding methyl-CpG-binding protein 2. We have created a mouse model (Mecp2 A140V “knock-in” mutant) expressing the recurrent human MECP2 A140V mutation linked to an X-linked mental retardation/Rett syndrome phenotype. Morphological analyses focused on quantifying soma and nucleus size were performed on primary hippocampus and cerebellum granule neuron (CGN) cultures from mutant (Mecp2A140V/y) and wild type (Mecp2+/y) male mice. Cultured hippocampus and cerebellar granule neurons from mutant animals were significantly smaller than neurons from wild type animals. We also examined soma size in hippocampus neurons from individual female transgenic mice that express both a mutant (maternal allele) and a wild type Mecp2 gene linked to an eGFP transgene (paternal allele). In cultures from such doubly heterozygous female mice, the size of neurons expressing the mutant (A140V) allele also showed a significant reduction compared to neurons expressing wild type MeCP2, supporting a cell-autonomous role for MeCP2 in neuronal development. IGF-1 (insulin growth factor-1) treatment of neuronal cells from Mecp2 mutant mice rescued the soma size phenotype. We also found that Mecp2 mutation leads to down-regulation of the mTOR signaling pathway, known to be involved in neuronal size regulation. Our results suggest that i) reduced neuronal size is an important in vitro cellular phenotype of Mecp2 mutation in mice, and ii) MeCP2 might play a critical role in the maintenance of neuronal structure by modulation of the mTOR pathway. The definition of a quantifiable cellular phenotype supports using neuronal size as a biomarker in the development of a high-throughput, in vitro assay to screen for compounds that rescue small neuronal phenotype (“phenotypic assay”).

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Pandey, Somnath, and Kevin Pruitt. "Functional assessment of MeCP2 in Rett syndrome and cancers of breast, colon, and prostate." Biochemistry and Cell Biology 95, no. 3 (June 2017): 368–78. http://dx.doi.org/10.1139/bcb-2016-0154.

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Ever since the first report that mutations in methyl-CpG-binding protein 2 (MeCP2) causes Rett syndrome (RTT), a severe neurological disorder in females world-wide, there has been a keen interest to gain a comprehensive understanding of this protein. While the classical model associated with MeCP2 function suggests its role in gene suppression via recruitment of co-repressor complexes and histone deacetylases to methylated CpG-sites, recent discoveries have brought to light its role in transcription activation, modulation of RNA splicing, and chromatin compaction. Various post-translational modifications (PTMs) of MeCP2 further increase its functional versatility. Involvement of MeCP2 in pathologies other than RTT, such as tumorigenesis however, remains poorly explored and understood. This review provides a survey of the literature implicating MeCP2 in breast, colon and prostate cancer.

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Ehinger, Yann, Valerie Matagne, Valérie Cunin, Emilie Borloz, Michel Seve, Sandrine Bourgoin-Voillard, Ana Borges-Correia, Laurent Villard, and Jean-Christophe Roux. "Analysis of Astroglial Secretomic Profile in the Mecp2-Deficient Male Mouse Model of Rett Syndrome." International Journal of Molecular Sciences 22, no. 9 (April 21, 2021): 4316. http://dx.doi.org/10.3390/ijms22094316.

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Mutations in the X-linked MECP2 gene are responsible for Rett syndrome (RTT), a severe neurological disorder. MECP2 is a transcriptional modulator that finely regulates the expression of many genes, specifically in the central nervous system. Several studies have functionally linked the loss of MECP2 in astrocytes to the appearance and progression of the RTT phenotype in a non-cell autonomous manner and mechanisms are still unknown. Here, we used primary astroglial cells from Mecp2-deficient (KO) pups to identify deregulated secreted proteins. Using a differential quantitative proteomic analysis, twenty-nine proteins have been identified and four were confirmed by Western blotting with new samples as significantly deregulated. To further verify the functional relevance of these proteins in RTT, we tested their effects on the dendritic morphology of primary cortical neurons from Mecp2 KO mice that are known to display shorter dendritic processes. Using Sholl analysis, we found that incubation with Lcn2 or Lgals3 for 48 h was able to significantly increase the dendritic arborization of Mecp2 KO neurons. To our knowledge, this study, through secretomic analysis, is the first to identify astroglial secreted proteins involved in the neuronal RTT phenotype in vitro, which could open new therapeutic avenues for the treatment of Rett syndrome.

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Li, Wei, Xin Xu, and Lucas Pozzo-Miller. "Excitatory synapses are stronger in the hippocampus of Rett syndrome mice due to altered synaptic trafficking of AMPA-type glutamate receptors." Proceedings of the National Academy of Sciences 113, no. 11 (February 29, 2016): E1575—E1584. http://dx.doi.org/10.1073/pnas.1517244113.

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Deficits in long-term potentiation (LTP) at central excitatory synapses are thought to contribute to cognitive impairments in neurodevelopmental disorders associated with intellectual disability and autism. Using the methyl-CpG-binding protein 2 (Mecp2) knockout (KO) mouse model of Rett syndrome, we show that naïve excitatory synapses onto hippocampal pyramidal neurons of symptomatic mice have all of the hallmarks of potentiated synapses. Stronger Mecp2 KO synapses failed to undergo LTP after either theta-burst afferent stimulation or pairing afferent stimulation with postsynaptic depolarization. On the other hand, basal synaptic strength and LTP were not affected in slices from younger presymptomatic Mecp2 KO mice. Furthermore, spine synapses in pyramidal neurons from symptomatic Mecp2 KO are larger and do not grow in size or incorporate GluA1 subunits after electrical or chemical LTP. Our data suggest that LTP is occluded in Mecp2 KO mice by already potentiated synapses. The higher surface levels of GluA1-containing receptors are consistent with altered expression levels of proteins involved in AMPA receptor trafficking, suggesting previously unidentified targets for therapeutic intervention for Rett syndrome and other MECP2-related disorders.

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Zlatanova, Jordanka. "MeCP2: the chromatin connection and beyond." Biochemistry and Cell Biology 83, no. 3 (June 1, 2005): 251–62. http://dx.doi.org/10.1139/o05-048.

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Of the recently discovered group of proteins that interpret DNA methylation signals by preferentially associating with methylated CpG dinucleotides, the methyl-CpG-binding protein 2 (MeCP2) has attracted considerable attention in view of its ability to repress transcription. The interest in MeCP2 dramatically increased following the discovery of mutated forms of the protein in patients with Rett syndrome, a neurodevelopmental disease. A connection with carcino-genesis has also been established. This review attempts to bring together and critically discuss recently acquired information about the molecular biology of the protein and its mechanism of action. A careful overview of the literature reveals the complexity of its activity, which goes well beyond the recognized chromatin connections. Finally, the newly established facts concerning the connection of MeCP2 to human disease are presented. Key words: methyl-CpG-binding proteins, MeCP2, transcription repression, chromatin modification, Rett syndrome, cancer.

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Buist, Marjorie, Nada El Tobgy, Danilo Shevkoplyas, Matthew Genung, Annan Ali Sher, Shervin Pejhan, and Mojgan Rastegar. "Differential Sensitivity of the Protein Translation Initiation Machinery and mTOR Signaling to MECP2 Gain- and Loss-of-Function Involves MeCP2 Isoform-Specific Homeostasis in the Brain." Cells 11, no. 9 (April 24, 2022): 1442. http://dx.doi.org/10.3390/cells11091442.

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Eukaryotic gene expression is controlled at multiple levels, including gene transcription and protein translation initiation. One molecule with key roles in both regulatory mechanisms is methyl CpG binding protein 2 (MeCP2). MECP2 gain- and loss-of-function mutations lead to Rett Syndrome and MECP2 Duplication Syndrome, respectively. To study MECP2 gain-of-function, we generated stably transduced human brain cells using lentiviral vectors for both MECP2E1 and MECP2E2 isoforms. Stable overexpression was confirmed by Western blot and immunofluorescence. We assessed the impact of MeCP2E1-E2 gain-of-function on the MeCP2 homeostasis regulatory network (MECP2E1/E2-BDNF/BDNF-miR-132), mTOR-AKT signaling, ribosome biogenesis, markers of chromatin structure, and protein translation initiation. We observed that combined co-transduction of MeCP2 isoforms led to protein degradation of MeCP2E1. Proteosome inhibition by MG132 treatment recovered MeCP2E1 protein within an hour, suggesting its induced degradation through the proteosome pathway. No significant change was detected for translation initiation factors as a result of MeCP2E1, MeCP2E2, or combined overexpression of both isoforms. In contrast, analysis of human Rett Syndrome brains tissues compared with controls indicated impaired protein translation initiation, suggesting that such mechanisms may have differential sensitivity to MECP2 gain- and loss-of-function. Collectively, our results provide further insight towards the dose-dependent functional role of MeCP2 isoforms in the human brain.

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De Filippis, Bianca, Mattia Musto, Luisa Altabella, Emilia Romano, Rossella Canese, and Giovanni Laviola. "Deficient Purposeful Use of Forepaws in Female Mice Modelling Rett Syndrome." Neural Plasticity 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/326184.

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Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases. Motor abnormalities represent a significant part of the spectrum of RTT symptoms. In the present study we investigated motor coordination and fine motor skill domains in MeCP2-308 female mice, a validated RTT model. This was complemented by thein vivomagnetic resonance spectroscopy (MRS) analysis of metabolic profile in behaviourally relevant brain areas. MeCP2-308 heterozygous female mice (Het, 10-12 months of age) were impaired in tasks validated for the assessment of purposeful and coordinated forepaw use (Morag testandCapellini handling task). A fine-grain analysis of spontaneous behaviour in the home-cage also revealed an abnormal handling pattern when interacting with the nesting material, reduced motivation to explore the environment, and increased time devoted to feeding in Het mice. The brain MRS evaluation highlighted decreased levels of bioenergetic metabolites in the striatal area in Het mice compared to controls. Present results confirm behavioural and brain alterations previously reported in MeCP2-308 males and identify novel endpoints on which the efficacy of innovative therapeutic strategies for RTT may be tested.

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Cortelazzo, Alessio, Claudio De Felice, Bianca De Filippis, Laura Ricceri, Giovanni Laviola, Silvia Leoncini, Cinzia Signorini, et al. "Persistent Unresolved Inflammation in the Mecp2-308 Female Mutated Mouse Model of Rett Syndrome." Mediators of Inflammation 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/9467819.

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Rett syndrome (RTT) is a rare neurodevelopmental disorder usually caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). Several Mecp2 mutant mouse lines have been developed recapitulating part of the clinical features. In particular, Mecp2-308 female heterozygous mice, bearing a truncating mutation, are a validated model of the disease. While recent data suggest a role for inflammation in RTT, little information on the inflammatory status in murine models of the disease is available. Here, we investigated the inflammatory status by proteomic 2-DE/MALDI-ToF/ToF analyses in symptomatic Mecp2-308 female mice. Ten differentially expressed proteins were evidenced in the Mecp2-308 mutated plasma proteome. In particular, 5 positive acute-phase response (APR) proteins increased (i.e., kininogen-1, alpha-fetoprotein, mannose-binding protein C, alpha-1-antitrypsin, and alpha-2-macroglobulin), and 3 negative APR reactants were decreased (i.e., serotransferrin, albumin, and apolipoprotein A1). CD5 antigen-like and vitamin D-binding protein, two proteins strictly related to inflammation, were also changed. These results indicate for the first time a persistent unresolved inflammation of unknown origin in the Mecp2-308 mouse model.

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Qiu, Z., E. L. Sylwestrak, D. N. Lieberman, Y. Zhang, X. Y. Liu, and A. Ghosh. "The Rett Syndrome Protein MeCP2 Regulates Synaptic Scaling." Journal of Neuroscience 32, no. 3 (January 18, 2012): 989–94. http://dx.doi.org/10.1523/jneurosci.0175-11.2012.

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Sheen, Volney, Isaac M. Valencia, and Alcy R. Torres. "Atypical Features in MECP2 P152R–Associated Rett Syndrome." Pediatric Neurology 49, no. 2 (August 2013): 124–26. http://dx.doi.org/10.1016/j.pediatrneurol.2012.12.037.

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Journal articles on the topic 'Rett syndrome MeCP2'

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