Materiały źródłowe

• #1 Rett syndrome: Genetics, clinical features, and diagnosis – UpToDate

  https://www.uptodate.com/contents/rett-syndrome-genetics-clinical-features-and-diagnosis/print

  Rett syndrome (RTT) is a severe neurodevelopmental disorder that occurs almost exclusively in females. […] Most cases result from pathogenic variants in the MECP2 gene. […] In most patients, RTT is caused by pathogenic variants in the MECP2 gene, which maps to Xq28 and encodes methyl-CpG binding protein 2 (MeCP2). […] Pathogenic variants in MECP2 have been detected in approximately 95 percent of classic sporadic RTT cases and 75 percent of atypical RTT cases. […] A minority of patients have atypical RTT caused by pathogenic variants in the CDKL5 or FOXG1 genes. […] There are three types of pathogenic variants in MECP2: missense, frameshift, and nonsense. The type of mutation may affect phenotypic expression.

• #2 Rett syndrome: Genetics, clinical features, and diagnosis – UpToDate

  https://www.uptodate.com/contents/rett-syndrome-genetics-clinical-features-and-diagnosis

  Rett syndrome (RTT) is a severe neurodevelopmental disorder that occurs almost exclusively in females. […] Most cases result from pathogenic variants in the MECP2 gene. […] In most patients, RTT is caused by pathogenic variants in the MECP2 gene, which maps to Xq28 and encodes methyl-CpG binding protein 2 (MeCP2). […] Pathogenic variants in MECP2 have been detected in approximately 95 percent of classic sporadic RTT cases and 75 percent of atypical RTT cases. […] There are three types of pathogenic variants in MECP2: missense, frameshift, and nonsense. The type of mutation may affect phenotypic expression.

• #3 Rett Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482252/

  Rett syndrome (RTT) is a neurodevelopmental disorder in which regression of previously acquired skills follows a period of typical development due to mutations of methylated CpG binding protein 2 (MECP2) gene on the X chromosome. RTT is associated with a complex phenotype and classified into typical, atypical, and variant presentations. Approximately 90% of reported cases of RTT inherit mutations of the MECP2 gene. Some atypical cases of RTT may result from mutations in cyclin-dependent kinase-like 5 (CDKL5). Mutations in MECP2 have been associated with impacting the development of neurons and axodendritic connections. […] RTT is an X-linked dominant condition with lethal consequences in hemizygous males. Recent studies mentioned that the majority of the RTT-causing variants in MECP2 are de novo and commonly on the paternally inherited X chromosome. The pathogenic MECP2 variants are identified in 95% of individuals with typical RTT. However, recent studies found that MeCP2, the protein product of MECP2, is known to regulate gene expression and is highly expressed in the brain.

• #4 Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-016-0545-5

  Rett syndrome (RTT) is a rare disease but still one of the most abundant causes for intellectual disability in females. A single mutation in one gene, coding for methyl-CpG-binding protein 2 (MECP2), is responsible for the disease. The most important action of MECP2 is regulating epigenetic imprinting and chromatin condensation, but MECP2 influences many different biological pathways on multiple levels although the molecular pathways from gene to phenotype are currently not fully understood. […] Recent research was able to find a correlation between certain MECP2 mutations (or MECP2 variants) and some phenotypes, e.g. cardiorespiratory phenotype, but most of the biological pathways between gene and phenotype are not yet fully understood. […] In summary, MECP2 affects epigenetic regulation of gene expression, which changes neurobiological activity, network formation and function, which causes the major phenotype.

• #5 Rett Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482252/

  Rett syndrome (RTT) is a neurodevelopmental disorder in which regression of previously acquired skills follows a period of typical development due to mutations of methylated CpG binding protein 2 (MECP2) gene on the X chromosome. RTT is associated with a complex phenotype and classified into typical, atypical, and variant presentations. Approximately 90% of reported cases of RTT inherit mutations of the MECP2 gene. Some atypical cases of RTT may result from mutations in cyclin-dependent kinase-like 5 (CDKL5). Mutations in MECP2 have been associated with impacting the development of neurons and axodendritic connections. […] RTT is an X-linked dominant condition with lethal consequences in hemizygous males. Recent studies mentioned that the majority of the RTT-causing variants in MECP2 are de novo and commonly on the paternally inherited X chromosome. The pathogenic MECP2 variants are identified in 95% of individuals with typical RTT. However, recent studies found that MeCP2, the protein product of MECP2, is known to regulate gene expression and is highly expressed in the brain.

• #6 Understanding Rett Syndrome | International Rett Syndrome Foundation

  https://www.rettsyndrome.org/about-rett-syndrome/understanding-rett-syndrome/

  Rett syndrome is a genetic disorder, caused by a spontaneous pathogenic variant or mutation in a gene called MECP2 that is located on the X chromosome. This gene is important for brain development and for activating and deactivating other gene functions. When the MECP2 gene does not function properly, it can cause issues throughout the entire body. […] These mutations usually occur spontaneously and are typically not inherited, making Rett syndrome a sporadic genetic condition. They result from random changes in the genetic code that happen around the time of conception. Importantly, these mutations are not caused by anything the parents did or didn’t do.

• #7 Rett Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482252/

  Rett syndrome (RTT) is a neurodevelopmental disorder in which regression of previously acquired skills follows a period of typical development due to mutations of methylated CpG binding protein 2 (MECP2) gene on the X chromosome. RTT is associated with a complex phenotype and classified into typical, atypical, and variant presentations. Approximately 90% of reported cases of RTT inherit mutations of the MECP2 gene. Some atypical cases of RTT may result from mutations in cyclin-dependent kinase-like 5 (CDKL5). Mutations in MECP2 have been associated with impacting the development of neurons and axodendritic connections. […] RTT is an X-linked dominant condition with lethal consequences in hemizygous males. Recent studies mentioned that the majority of the RTT-causing variants in MECP2 are de novo and commonly on the paternally inherited X chromosome. The pathogenic MECP2 variants are identified in 95% of individuals with typical RTT. However, recent studies found that MeCP2, the protein product of MECP2, is known to regulate gene expression and is highly expressed in the brain.

• #8 Rett syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Rett_syndrome

  Rett syndrome is due to a genetic mutation in the MECP2 gene, on the X chromosome. […] In less than 10% of RTT cases, mutations in the genes CDKL5 or FOXG1 have also been found to resemble it. […] A 2021 study by scholars based at Scottish universities states that Rett syndrome is in fact a neurodevelopmental condition as opposed to a neurodegenerative condition. One piece of evidence for this is that mice with induced Rett syndrome show no neuronal death, and some studies have suggested that their phenotypes can be partially rescued by adding functional MECP2 gene back when they are adults. […] The genetic loss of MECP2 changes the properties of cells in the locus coeruleus, 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 coeruleus is a critical site at which loss of MECP2 results in CNS dysfunction.”

• #9 Rett syndrome: Genetics, clinical features, and diagnosis – UpToDate

  https://www.uptodate.com/contents/rett-syndrome-genetics-clinical-features-and-diagnosis/print

  Rett syndrome (RTT) is a severe neurodevelopmental disorder that occurs almost exclusively in females. […] Most cases result from pathogenic variants in the MECP2 gene. […] In most patients, RTT is caused by pathogenic variants in the MECP2 gene, which maps to Xq28 and encodes methyl-CpG binding protein 2 (MeCP2). […] Pathogenic variants in MECP2 have been detected in approximately 95 percent of classic sporadic RTT cases and 75 percent of atypical RTT cases. […] A minority of patients have atypical RTT caused by pathogenic variants in the CDKL5 or FOXG1 genes. […] There are three types of pathogenic variants in MECP2: missense, frameshift, and nonsense. The type of mutation may affect phenotypic expression.

• #10 Rett Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482252/

  Rett syndrome (RTT) is a neurodevelopmental disorder in which regression of previously acquired skills follows a period of typical development due to mutations of methylated CpG binding protein 2 (MECP2) gene on the X chromosome. RTT is associated with a complex phenotype and classified into typical, atypical, and variant presentations. Approximately 90% of reported cases of RTT inherit mutations of the MECP2 gene. Some atypical cases of RTT may result from mutations in cyclin-dependent kinase-like 5 (CDKL5). Mutations in MECP2 have been associated with impacting the development of neurons and axodendritic connections. […] RTT is an X-linked dominant condition with lethal consequences in hemizygous males. Recent studies mentioned that the majority of the RTT-causing variants in MECP2 are de novo and commonly on the paternally inherited X chromosome. The pathogenic MECP2 variants are identified in 95% of individuals with typical RTT. However, recent studies found that MeCP2, the protein product of MECP2, is known to regulate gene expression and is highly expressed in the brain.

• #11 Rett Syndrome: Practice Essentials, Background, Pathophysiology and Etiology

  https://emedicine.medscape.com/article/916377-overview

  About 70% of RS cases are due to 4 missense mutations (ie, R106W, R133C, T158M, R306C) and 4 nonsense protein-truncating mutations (ie, R168X, R255X, R270X, R294X), which are large deletions that cause significant gene destruction, resulting in greater severity. Another cluster of mutations near the end of the gene abrogate only the very end of the protein (C-terminal truncations). Physical therapy and speech therapy may result in intragroup differences, causing different outcomes. […] RS is the first human disease determined to be caused by defects in a protein that regulates gene expression through interaction with methylated DNA. Accordingly, it involves abnormal chromatin structure, with broad-ranging effects on expression of genes that are otherwise not mutated. The normal MECP2 gene encodes the MECP2 protein, which binds to methylated DNA in conjunction with a corepressor. This causes activation of histone deacetylase.

• #12 Rett Syndrome: Practice Essentials, Background, Pathophysiology and Etiology

  https://emedicine.medscape.com/article/916377-overview

  Mutations in the MECP2 gene produce loss of function of this protein and unregulated expression of the genes that it normally affects, some of which appear to be crucial in nervous system development beyond the initial stages. Although the nervous system is the primary site, the specific target genes are not known. Astrocyte function is abnormal in RS, presumably owing to dysfunction of the MECP2 gene. […] A study of 974 RS patients was conducted using data from databases that employed multiplex ligation-dependent probe amplification (MLPA) to detect large deletions on MECP2. Those with large deletions were less likely to have learned to walk, were not walking, and were more likely to have the most severe gross motor dysfunction and epilepsy; they also appeared to develop epilepsy, scoliosis, hand stereotypies and abnormal breathing patterns at an earlier age. These findings may help predict age of onset and symptom severity in RS.

• #13 Rett Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482252/

  Furthermore, 2 additional genes, cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1), are involved in the pathogenesis of RTT. The spectrum of mutation types includes missense, nonsense, and frameshift mutations. Mutations affecting the NLS region of MECP2 or early truncating mutations are responsible for a more severe phenotype than missense mutations, whereas C-terminal deletions are associated with milder phenotypes. The R133C mutation is generally associated with a milder variant of RTT, often with preserved speech. […] Recent studies also suggested that MECP2 has both repressor and activator transcription activities. The exact mechanism of how MECP2 mutations lead to RTT is unknown. A possible theory is that a deficiency of MECP2 causes an inability of synaptic maturation in the cortex. Another hypothesis is that lack of MECP2 disrupts brain cholesterol metabolism, resulting in abnormal neuronal development. One of the studies found that the MECP2 acts as a positive cofactor for RNA Pol II gene expression at many neuronal genes that harbor CpG islands in promoter-proximal regions and that RTT is due partly to the loss of gene activity of these genes in neurons.

• #14 Rett Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482252/

  Furthermore, 2 additional genes, cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1), are involved in the pathogenesis of RTT. The spectrum of mutation types includes missense, nonsense, and frameshift mutations. Mutations affecting the NLS region of MECP2 or early truncating mutations are responsible for a more severe phenotype than missense mutations, whereas C-terminal deletions are associated with milder phenotypes. The R133C mutation is generally associated with a milder variant of RTT, often with preserved speech. […] Recent studies also suggested that MECP2 has both repressor and activator transcription activities. The exact mechanism of how MECP2 mutations lead to RTT is unknown. A possible theory is that a deficiency of MECP2 causes an inability of synaptic maturation in the cortex. Another hypothesis is that lack of MECP2 disrupts brain cholesterol metabolism, resulting in abnormal neuronal development. One of the studies found that the MECP2 acts as a positive cofactor for RNA Pol II gene expression at many neuronal genes that harbor CpG islands in promoter-proximal regions and that RTT is due partly to the loss of gene activity of these genes in neurons.

• #15 Rett Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482252/

  Furthermore, 2 additional genes, cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1), are involved in the pathogenesis of RTT. The spectrum of mutation types includes missense, nonsense, and frameshift mutations. Mutations affecting the NLS region of MECP2 or early truncating mutations are responsible for a more severe phenotype than missense mutations, whereas C-terminal deletions are associated with milder phenotypes. The R133C mutation is generally associated with a milder variant of RTT, often with preserved speech. […] Recent studies also suggested that MECP2 has both repressor and activator transcription activities. The exact mechanism of how MECP2 mutations lead to RTT is unknown. A possible theory is that a deficiency of MECP2 causes an inability of synaptic maturation in the cortex. Another hypothesis is that lack of MECP2 disrupts brain cholesterol metabolism, resulting in abnormal neuronal development. One of the studies found that the MECP2 acts as a positive cofactor for RNA Pol II gene expression at many neuronal genes that harbor CpG islands in promoter-proximal regions and that RTT is due partly to the loss of gene activity of these genes in neurons.

• #16 New findings activate a better understanding of Rett syndrome’s causes | Whitehead Institute

  https://wi.mit.edu/news/new-findings-activate-better-understanding-rett-syndrome-s-causes

  Rett syndrome is caused by mutations to the gene MECP2, which is highly expressed in the brain and appears to play important roles in maintaining healthy neurons. […] The MECP2 protein encoded by the gene is involved in gene regulation; it binds to DNA and affects the expression level of various other genesmeaning the amount of protein produced from them. […] Early research into MECP2 suggested that it was a repressor, decreasing the expression of its target genes, but research by Jaenisch and others previously found that MECP2 also acts as an activator, increasing its targets expressionand that it might primarily be an activator. […] One new experiment indicated that MECP2 activates at least 80% of its targets, and another indicated that it activates as many as 88% of its targets. […] The researchers propose that MECP2 serves as one such cofactor, helping RNA Pol II to initiate transcription at the genes where MECP2 binds.

• #17 Rett Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482252/

  Furthermore, 2 additional genes, cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1), are involved in the pathogenesis of RTT. The spectrum of mutation types includes missense, nonsense, and frameshift mutations. Mutations affecting the NLS region of MECP2 or early truncating mutations are responsible for a more severe phenotype than missense mutations, whereas C-terminal deletions are associated with milder phenotypes. The R133C mutation is generally associated with a milder variant of RTT, often with preserved speech. […] Recent studies also suggested that MECP2 has both repressor and activator transcription activities. The exact mechanism of how MECP2 mutations lead to RTT is unknown. A possible theory is that a deficiency of MECP2 causes an inability of synaptic maturation in the cortex. Another hypothesis is that lack of MECP2 disrupts brain cholesterol metabolism, resulting in abnormal neuronal development. One of the studies found that the MECP2 acts as a positive cofactor for RNA Pol II gene expression at many neuronal genes that harbor CpG islands in promoter-proximal regions and that RTT is due partly to the loss of gene activity of these genes in neurons.

• #18 Rett Syndrome: Practice Essentials, Background, Pathophysiology and Etiology

  https://emedicine.medscape.com/article/916377-overview

  Rett syndrome (RS) is a genetic disorder of neurodevelopmental arrest rather than a progressive process. The gene is located on the X chromosome. Females with a single mutated MECP2 gene are more likely to survive because 1 X chromosome is activated randomly in each cell. […] The symptoms and severity of RS may depend on both the percentage of activated defective genes and the type of mutation. Multiple mutation types have been found in the 3 coding regions of the MECP2 gene, with most of them causing truncations and missense proteins. Mutations have been found in as many as 80% of analyzed cases of classic RS. The MECP2 protein may act as a transcriptional repressor or activator, depending on the target gene with which it associates. […] The mutations that cause RS are almost all sporadic. In families with a girl who has RS, the increased risk of having a second girl with the syndrome is reportedly less than 0.4%. However, recurrence in families can occur through mechanisms such as germline mosaicism.

• #19 New findings activate a better understanding of Rett syndrome’s causes | Whitehead Institute

  https://wi.mit.edu/news/new-findings-activate-better-understanding-rett-syndrome-s-causes

  Rett syndrome is caused by mutations to the gene MECP2, which is highly expressed in the brain and appears to play important roles in maintaining healthy neurons. […] The MECP2 protein encoded by the gene is involved in gene regulation; it binds to DNA and affects the expression level of various other genesmeaning the amount of protein produced from them. […] Early research into MECP2 suggested that it was a repressor, decreasing the expression of its target genes, but research by Jaenisch and others previously found that MECP2 also acts as an activator, increasing its targets expressionand that it might primarily be an activator. […] One new experiment indicated that MECP2 activates at least 80% of its targets, and another indicated that it activates as many as 88% of its targets. […] The researchers propose that MECP2 serves as one such cofactor, helping RNA Pol II to initiate transcription at the genes where MECP2 binds.

• #20 New findings activate a better understanding of Rett syndrome’s causes | Whitehead Institute

  https://wi.mit.edu/news/new-findings-activate-better-understanding-rett-syndrome-s-causes

  This suggests that Rett syndrome may be caused by a decrease in transcription of the genes targeted by MECP2, due to MECP2 mutations that prevent it from binding RNA Pol II or binding DNA. […] Consistent with this idea, most of the common disease-linked MECP2 mutations are truncations: mutations in which part of the protein is missing, which may alter the interaction between MECP2 and RNA Pol II.

• #21 Molecular Mechanisms of Rett Syndrome: Emphasizing the Roles of Monoamine, Immunity, and Mitochondrial Dysfunction

  https://www.mdpi.com/2073-4409/13/24/2077

  Rett syndrome (RTT), which predominantly affects females, arises in most cases from mutations in the Methyl-CpG-binding Protein-2 (MECP2) gene. When MeCP2 is impaired, it disrupts the regulation of numerous genes, causing the production of dysfunctional proteins associated with various multi-systemic issues in RTT. […] Research has shown that monoamines—such as dopamine, norepinephrine, epinephrine, serotonin, and histamine—exhibit alterations in RTT, contributing to a range of neurological symptoms. Furthermore, the immune system in RTT individuals demonstrates dysfunction through the abnormal activity of microglia, macrophages, lymphocytes, and non-immune cells, leading to the atypical release of inflammatory mediators and disruptions in the NF-κB signaling pathway. Moreover, mitochondria, essential for energy production and calcium storage, also show dysfunction in this condition. The delicate balance of producing and scavenging reactive oxygen species—termed redox balance—is disrupted in RTT. Targeting these molecular pathways presents a promising avenue for developing effective therapies.

• #22 Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease

  https://www.mdpi.com/2218-273X/11/1/75

  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 de novo mutation(s) in the Methyl-CpG-Binding Protein 2 (MECP2) gene. […] MeCP2 function was originally studied in nerve cells (neurons). However, later research highlighted its importance in other cell types of the brain including glia. […] 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 (miR132) and brain-derived neurotrophic factor (BDNF).

• #23 Rett Syndrome Astrocytes Are Abnormal and Spread MeCP2 Deficiency through Gap Junctions | Journal of Neuroscience

  https://www.jneurosci.org/content/29/16/5051

  MECP2, an X-linked gene encoding the epigenetic factor methyl-CpG-binding protein-2, is mutated in Rett syndrome (RTT) and aberrantly expressed in autism. […] While prior functional investigations of MeCP2 have focused exclusively on neurons and have concluded the absence of MeCP2 in astrocytes, here we report that astrocytes express MeCP2, and MeCP2 deficiency in astrocytes causes significant abnormalities in BDNF regulation, cytokine production, and neuronal dendritic induction, effects that may contribute to abnormal neurodevelopment. […] In addition, we show that the MeCP2 deficiency state can progressively spread at least in part via gap junction communications between mosaic Mecp2 /+ astrocytes in a novel non-cell-autonomous mechanism. […] Our results suggest that astrocytes are viable therapeutic targets for RTT and perhaps regressive forms of autism.

• #24 MeCP2 Deficiency in Neuroglia: New Progress in the Pathogenesis of Rett Syndrome

  https://patrinum.ch/record/433182?ln=en

  Rett syndrome (RTT) is an X-linked neurodevelopmental disease predominantly caused by mutations of the methyl-CpG-binding protein 2 (MeCP2) gene. […] However, increasing evidence has shown that glial abnormalities are also involved in the pathogenesis of RTT. Mice that are MeCP2-null specifically in glial cells showed similar behavioral and/or neuronal abnormalities as those found in MeCP2-null mice, a mouse model of RTT. MeCP2 deficiency in astrocytes impacts the expression of glial intermediate filament proteins such as fibrillary acidic protein (GFAP) and S100 and induces neuron toxicity by disturbing glutamate metabolism or enhancing microtubule instability. MeCP2 deficiency in oligodendrocytes (OLs) results in down-regulation of myelin gene expression and impacts myelination. While MeCP2-deficient microglia cells fail in response to environmental stimuli, release excessive glutamate, and aggravate impairment of the neuronal circuit. […] In this review, we mainly focus on the progress in determining the role of MeCP2 in glial cells involved in RTT, which may provide further insight into a therapeutic intervention for RTT.

• #25 Mechanism and consequence of abnormal calcium homeostasis in Rett syndrome astrocytes | eLife

  https://elifesciences.org/articles/33417

  Astrocytes play an important role in Rett syndrome (RTT) disease progression. […] We report that spontaneous calcium activity is abnormal in RTT astrocytes in vitro, in situ, and in vivo. Such abnormal calcium activity is mediated by calcium overload in the endoplasmic reticulum caused by abnormal store operated calcium entry, which is in part dependent on elevated expression of TRPC4. […] Our findings provide evidence that abnormal calcium homeostasis is a key cell-autonomous phenotype in RTT astrocytes, and reveal its mechanism and consequence. […] We observed abnormal spontaneous and pharmacologically evoked cytosolic calcium activities in cultured mutant RTT astrocytes, when compared to their congenic wild type controls. […] Moreover, we report that these abnormal calcium activities are mediated by calcium overload in the endoplasmic reticulum (ER), which is caused by abnormal TRPC4-dependent store operated calcium entry (SOCE). […] Together, these results strongly suggest that elevated TRPC4 expression is required for the abnormal calcium homeostasis in MeCP2 deficient astrocytes. […] Our findings provide a direct functional link between astrocyte dysfunction and neuronal dysfunction in RTT.

• #26 MeCP2 Deficiency in Neuroglia: New Progress in the Pathogenesis of Rett Syndrome

  https://patrinum.ch/record/433182?ln=en

  Rett syndrome (RTT) is an X-linked neurodevelopmental disease predominantly caused by mutations of the methyl-CpG-binding protein 2 (MeCP2) gene. […] However, increasing evidence has shown that glial abnormalities are also involved in the pathogenesis of RTT. Mice that are MeCP2-null specifically in glial cells showed similar behavioral and/or neuronal abnormalities as those found in MeCP2-null mice, a mouse model of RTT. MeCP2 deficiency in astrocytes impacts the expression of glial intermediate filament proteins such as fibrillary acidic protein (GFAP) and S100 and induces neuron toxicity by disturbing glutamate metabolism or enhancing microtubule instability. MeCP2 deficiency in oligodendrocytes (OLs) results in down-regulation of myelin gene expression and impacts myelination. While MeCP2-deficient microglia cells fail in response to environmental stimuli, release excessive glutamate, and aggravate impairment of the neuronal circuit. […] In this review, we mainly focus on the progress in determining the role of MeCP2 in glial cells involved in RTT, which may provide further insight into a therapeutic intervention for RTT.

• #27

  https://omim.org/entry/312750

  Marchetto et al. (2010) generated neurons with RTT-associated MECP2 mutations from induced pluripotent stem cells derived from fibroblasts isolated from patients with Rett syndrome. These cells were able to undergo X inactivation and generate functional neurons. Studies of these neurons in culture showed fewer synapses, reduced spine density, and small soma size compared to controls. In addition, these cells showed altered calcium signaling and electrophysiologic defects, particularly affecting glutamate signaling, compared to controls. The findings demonstrated that human RTT neurons have early developmental defects. Pharmacologic treatment of these cells with IGF1 (147440) and gentamicin, which causes read-through of nonsense mutations, showed some promising results. […] Muotri et al. (2010) showed that L1 neuronal transcription and retrotransposition in rodents are increased in the absence of Mecp2. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, they revealed that patients with Rett syndrome, carrying MeCP2 mutations, have increased susceptibility for L1 retrotransposition. Muotri et al. (2010) concluded that L1 retrotransposition can be controlled in a tissue-specific manner and that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition.

• #28 The Pathophysiology of Rett Syndrome With a Focus on Breathing Dysfunctions

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7864239/

  We will emphasize that what makes RTT complex is not only the complexity of the MECP2 mutation itself but the feedback-laden nature of physiology, which includes changes in metabolic regulation and oxygen homeostasis. […] Although the neuronal consequences of MECP2 mutations are the major driver of the known clinical phenotypes, ultimately, pathologies induced by MECP2 mutations are not only restricted to the brain; they affect the entire physiology, resulting in an interplay that contributes to the complexity of the clinical phenotype. […] Important drivers of the RTT pathophysiology are mitochondrial and inflammatory dysfunctions. Targeting specific pathophysiological dysfunctions in RTT shows great therapeutic promise, yet this specific approach may not suffice to reestablish all the interacting dysregulations that are the hallmark of RTT.

• #29 Molecular Mechanisms of Rett Syndrome: Emphasizing the Roles of Monoamine, Immunity, and Mitochondrial Dysfunction

  https://www.mdpi.com/2073-4409/13/24/2077

  Ample evidence highlights the significant role of the transcription factor NF-κB in RTT. Studies have shown that the deletion of MeCP2 from PBMCs, the human monocyte line THP1, or the mouse cortex led to an increase in NF-κB expression. […] Mitochondria are organelles primarily involved in ATP production, but also play essential roles in other critical processes like calcium storage, apoptosis, and notably, immune response and inflammation. […] RTT has been associated with mitochondrial dysfunction due to the occurrence of redox imbalance in the brains of presymptomatic Mecp2-deficient mice. Several studies have indicated an increase in OS markers in RTT patients and mouse models, coupled with a diminished scavenging system. […] Given the severity of mitochondrial dysfunction and its clear association with RTT, identifying potential therapeutic targets is crucial.

• #30 Molecular Mechanisms of Rett Syndrome: Emphasizing the Roles of Monoamine, Immunity, and Mitochondrial Dysfunction

  https://www.mdpi.com/2073-4409/13/24/2077

  Ample evidence highlights the significant role of the transcription factor NF-κB in RTT. Studies have shown that the deletion of MeCP2 from PBMCs, the human monocyte line THP1, or the mouse cortex led to an increase in NF-κB expression. […] Mitochondria are organelles primarily involved in ATP production, but also play essential roles in other critical processes like calcium storage, apoptosis, and notably, immune response and inflammation. […] RTT has been associated with mitochondrial dysfunction due to the occurrence of redox imbalance in the brains of presymptomatic Mecp2-deficient mice. Several studies have indicated an increase in OS markers in RTT patients and mouse models, coupled with a diminished scavenging system. […] Given the severity of mitochondrial dysfunction and its clear association with RTT, identifying potential therapeutic targets is crucial.

• #31 Rett Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482252/

  Studies have also suggested that the failure of dendritic arborization in the cortex has led to abnormal neuronal signaling, resulting in the lack of maturation of the autonomic nervous system and the motor and cortical regions. Recent evidence suggests that MECP2 is also expressed in glial cells and glial cell dysfunction caused by a change in DNA methylation could also be involved in the pathogenesis of RTT. MECP2 mutation affects mitochondrial and metabolic pathways in astrocytes thereby affecting neuronal health. The smaller mitochondria particularly in glia versus neurons resulted in decreased mitochondrial respiration and altered key proteins in the tricarboxylic acid cycle and electron transport chain in RTT patients. Moreover, RTT astrocytes demonstrated increased cytosolic amino acids under basal conditions, which were low when energy demands were high. The mitochondria isolated from astrocytes of RTT patients exhibited increased reactive oxygen species and influenced neuronal activity when transferred to cortical neurons.

• #32 Rett Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482252/

  Studies have also suggested that the failure of dendritic arborization in the cortex has led to abnormal neuronal signaling, resulting in the lack of maturation of the autonomic nervous system and the motor and cortical regions. Recent evidence suggests that MECP2 is also expressed in glial cells and glial cell dysfunction caused by a change in DNA methylation could also be involved in the pathogenesis of RTT. MECP2 mutation affects mitochondrial and metabolic pathways in astrocytes thereby affecting neuronal health. The smaller mitochondria particularly in glia versus neurons resulted in decreased mitochondrial respiration and altered key proteins in the tricarboxylic acid cycle and electron transport chain in RTT patients. Moreover, RTT astrocytes demonstrated increased cytosolic amino acids under basal conditions, which were low when energy demands were high. The mitochondria isolated from astrocytes of RTT patients exhibited increased reactive oxygen species and influenced neuronal activity when transferred to cortical neurons.

• #33 Molecular Mechanisms of Rett Syndrome: Emphasizing the Roles of Monoamine, Immunity, and Mitochondrial Dysfunction

  https://www.mdpi.com/2073-4409/13/24/2077

  Most RTT cases are known to stem from mutations in the methyl-CpG-binding protein 2 (MECP2) gene. This gene is essential for regulating the expression of numerous genes in the brain and beyond, resulting in significant disruptions in cellular function that can lead to various multi-systemic comorbidities. […] This review will delve into the current understanding of monoamines, cell immunity, and mitochondrial function in RTT, three domains that are recently receiving increased attention due to their interconnected signaling and metabolic pathways that, when dysfunctional, underpin the molecular mechanisms involved in RTT pathophysiology. […] Growing evidence demonstrates that dysfunctional immunity and subclinical inflammation are the significant pathophysiological mechanisms contributing to the progression of RTT.

• #34 Uncovering the genetic mechanism behind Rett syndrome

  https://medicalxpress.com/news/2021-07-uncovering-genetic-mechanism-rett-syndrome.html

  Medical researchers led by Kyushu University have revealed a possible underlying genetic pathway behind the neurological dysfunction of Rett syndrome. The team found that deficiencies in key genes involved in the pathology triggers neural stem cells to generate less neurons by producing more astrocytes—the brain’s maintenance cells. […] The researchers hope that the molecular pathology they identified, as reported in the journal Cell Reports, can lead to potential therapeutic targets for Rett syndrome in the future. […] „Rett syndrome is caused by mutations in a single gene called methyl-CpG binding protein 2, or MeCP2. The gene was identified over two decades ago and much has been uncovered since, but exactly how the mutations cause the pathology remains elusive,” explains first author Hideyuki Nakashima of Kyushu University’s Faculty of Medical Sciences.

• #35 Uncovering the genetic mechanism behind Rett syndrome

  https://medicalxpress.com/news/2021-07-uncovering-genetic-mechanism-rett-syndrome.html

  „Through our investigation, we found several microRNAs associated with MeCP2, but only one affected the differentiation of neural stem cells: a microRNA called miR-199a,” says Nakashima. „In fact, when either MeCP2 or miR-199a are disrupted, we found that it increased the production of cells called astrocytes.” […] „Further analysis showed that miR-199a targets the protein Smad1, a transcription factor critical for proper cellular development. Smad1 functions downstream of a pathway called BMP signaling, which is known to inhibit the production of neurons and facilitate the generation of astrocytes,” states Nakashima. […] „Our findings have given us valuable insight into the role of MeCP2, miR-199a, and BMP signaling in the pathology of Rett syndrome,” concludes Kinichi Nakashima, who headed the team. „Further investigation is needed, but we hope this can lead to clinical treatments for Rett syndrome symptoms.”

• #36 Uncovering the genetic mechanism behind Rett syndrome | Research Results | KYUSHU UNIVERSITY

  https://www.kyushu-u.ac.jp/en/researches/view/214/

  Dysfunction in key gene causes neural stem cells to produce more astrocytes than neurons. […] The team found that deficiencies in key genes involved in the pathology triggers neural stem cells to generate less neurons by producing more astrocytes the brain’s maintenance cells. […] „Rett syndrome is caused by mutations in a single gene called methyl-CpG binding protein 2, or MeCP2.” […] „Through our investigation, we found several microRNAs associated with MeCP2, but only one affected the differentiation of neural stem cells: a microRNA called miR-199a.” […] „In fact, when either MeCP2 or miR-199a are disrupted, we found that it increased the production of cells called astrocytes.” […] „Further analysis showed that miR-199a targets the protein Smad1, a transcription factor critical for proper cellular development.” […] „Smad1 functions downstream of a pathway called BMP signaling, which is known to inhibit the production of neurons and facilitate the generation of astrocytes.” […] „Our findings have given us valuable insight into the role of MeCP2, miR-199a, and BMP signaling in the pathology of Rett syndrome.”

• #37 A novel pathway in the pathology of Rett syndrome

  https://frontlinegenomics.com/a-novel-pathway-in-the-pathology-of-rett-syndrome/

  Researchers have revealed how dysregulation of the MECP2/miR-199a axis may contribute to the molecular pathology of Rett syndrome. […] RTT arises from loss-of-function mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene. MECP2 has previously been demonstrated to facilitate post-transcriptional processing of miR-199a, a miRNA regulating neuronal function. […] A recent paper, published in Cell Reports, revealed that MECP2 and miR-199a may act together to regulate neuronal differentiation. […] This suggests that perturbations in the MECP2/miR-199a axis skews NS/PC differentiation from neuronal to astrocytic. […] Altogether, these results suggest that MECP2 suppresses SMAD1 via miR-199a interference. As a result, MECP2 and miR-199a deficiency may lead to overexpression of SMAD1 and BMP signalling, which ultimately leads to impaired brain development in RTT patients. […] These observations have not only supported dysregulation of the MECP2/miR-199a/SMAD1 axis in RTT pathogenesis. But they have also pointed to a novel therapeutic target that may eventually lead to efficacious RTT treatments.

• #38 Rett syndrome: Genetics, clinical features, and diagnosis – UpToDate

  https://www.uptodate.com/contents/rett-syndrome-genetics-clinical-features-and-diagnosis/print

  Rett syndrome (RTT) is a severe neurodevelopmental disorder that occurs almost exclusively in females. […] Most cases result from pathogenic variants in the MECP2 gene. […] In most patients, RTT is caused by pathogenic variants in the MECP2 gene, which maps to Xq28 and encodes methyl-CpG binding protein 2 (MeCP2). […] Pathogenic variants in MECP2 have been detected in approximately 95 percent of classic sporadic RTT cases and 75 percent of atypical RTT cases. […] A minority of patients have atypical RTT caused by pathogenic variants in the CDKL5 or FOXG1 genes. […] There are three types of pathogenic variants in MECP2: missense, frameshift, and nonsense. The type of mutation may affect phenotypic expression.

• #39 A step closer to understanding Rett syndrome

  https://www.carrerasresearch.org/en/news/a-step-closer-to-understanding-rett-syndrome

  In the research, first-authored by Dr. Edilene Siqueira and recently published in the longstanding scientific journal Nucleic Acids Research, the team used the latest genetic tools available, such as single-cell RNA sequencing and CRISPR/Cas9 gene editing technology, and found that mutations in MeCP2 led to the depletion of a long non-coding RNA called NEAT1. As it turns out, NEAT1 controls the autophagy system by establishing direct RNA-RNA contacts with components of its machinery and directing their localization within the cell. Consequently, NEAT1 deficiency contributes to some of the cellular alterations found in Rett syndrome. […] Furthermore, the team demonstrated that restoring NEAT1 could reverse these alterations in in vitro models of the disease, opening the door to the exploration of new therapeutic approaches in the coming years.

• #40 CREB Signaling Is Involved in Rett Syndrome Pathogenesis | Journal of Neuroscience

  https://www.jneurosci.org/content/37/13/3671

  Rett syndrome (RTT) is a debilitating neurodevelopmental disorder caused by mutations in the MECP2 gene. […] Detailed analyses of forebrain neurons differentiated from these human stem cell lines revealed genotype-dependent quantitative phenotypes in neurite growth, dendritic complexity, and mitochondrial function. […] At the molecular level, we found a significant reduction in the level of CREB and phosphorylated CREB in forebrain neurons differentiated from MECP2T158M/T158M, MECP2-KO, and V247fs-MT stem cell lines. […] Importantly, overexpression of CREB or pharmacological activation of CREB signaling in those forebrain neurons rescued the phenotypes in neurite growth, dendritic complexity, and mitochondrial function. […] Together, our study establishes a robust in vitro platform for consistent quantitative evaluation of genotype-dependent RTT phenotypes, reveals a previously unappreciated role of CREB signaling in RTT pathogenesis, and identifies a potential therapeutic target for RTT.

• #41 CREB Signaling Is Involved in Rett Syndrome Pathogenesis | Journal of Neuroscience

  https://www.jneurosci.org/content/37/13/3671

  Rett syndrome (RTT) is a debilitating neurodevelopmental disorder caused by mutations in the MECP2 gene. […] Detailed analyses of forebrain neurons differentiated from these human stem cell lines revealed genotype-dependent quantitative phenotypes in neurite growth, dendritic complexity, and mitochondrial function. […] At the molecular level, we found a significant reduction in the level of CREB and phosphorylated CREB in forebrain neurons differentiated from MECP2T158M/T158M, MECP2-KO, and V247fs-MT stem cell lines. […] Importantly, overexpression of CREB or pharmacological activation of CREB signaling in those forebrain neurons rescued the phenotypes in neurite growth, dendritic complexity, and mitochondrial function. […] Together, our study establishes a robust in vitro platform for consistent quantitative evaluation of genotype-dependent RTT phenotypes, reveals a previously unappreciated role of CREB signaling in RTT pathogenesis, and identifies a potential therapeutic target for RTT.

• #42 CREB Signaling Is Involved in Rett Syndrome Pathogenesis | Journal of Neuroscience

  https://www.jneurosci.org/content/37/13/3671

  Although defects in dendritic morphology and mitochondrial function have been observed in patient biopsies and RTT models, the role of CREB in RTT pathogenesis has not been directly investigated. […] Our study substantially extends these previous reports by providing the first functional evidence that reduced CREB expression is responsible for key RTT pathologies at the cellular level. […] Specifically, we showed that overexpression of CREB in MECP2 mutant neurons is sufficient to rescue the phenotypes of reduced neuronal growth, mitochondrial fragmentation, and lower MMP. […] Together, these results strongly suggest that reduced CREB expression is a key contributor to the phenotypes of reduced neuronal growth and impaired mitochondrial health in MECP2 mutant neurons. […] Our work not only provides a foundation for further investigating the molecular basis of mitochondrial defects in RTT but also identifies a robust disease phenotype (reduced MMP) and a convenient assay (the JC-10 assay) that can be used to screen candidate drugs in the future. […] By showing that chronic treatment with rolipram can alleviate some behavioral phenotypes in the female Mecp2/+ mice, we illustrate the potential of CREB signaling as a molecular target for treating RTT.

• #43 Molecular Mechanisms of Rett Syndrome: Emphasizing the Roles of Monoamine, Immunity, and Mitochondrial Dysfunction

  https://www.mdpi.com/2073-4409/13/24/2077

  Ample evidence highlights the significant role of the transcription factor NF-κB in RTT. Studies have shown that the deletion of MeCP2 from PBMCs, the human monocyte line THP1, or the mouse cortex led to an increase in NF-κB expression. […] Mitochondria are organelles primarily involved in ATP production, but also play essential roles in other critical processes like calcium storage, apoptosis, and notably, immune response and inflammation. […] RTT has been associated with mitochondrial dysfunction due to the occurrence of redox imbalance in the brains of presymptomatic Mecp2-deficient mice. Several studies have indicated an increase in OS markers in RTT patients and mouse models, coupled with a diminished scavenging system. […] Given the severity of mitochondrial dysfunction and its clear association with RTT, identifying potential therapeutic targets is crucial.

• #44 Molecular Mechanisms of Rett Syndrome: Emphasizing the Roles of Monoamine, Immunity, and Mitochondrial Dysfunction

  https://www.mdpi.com/2073-4409/13/24/2077

  Most RTT cases are known to stem from mutations in the methyl-CpG-binding protein 2 (MECP2) gene. This gene is essential for regulating the expression of numerous genes in the brain and beyond, resulting in significant disruptions in cellular function that can lead to various multi-systemic comorbidities. […] This review will delve into the current understanding of monoamines, cell immunity, and mitochondrial function in RTT, three domains that are recently receiving increased attention due to their interconnected signaling and metabolic pathways that, when dysfunctional, underpin the molecular mechanisms involved in RTT pathophysiology. […] Growing evidence demonstrates that dysfunctional immunity and subclinical inflammation are the significant pathophysiological mechanisms contributing to the progression of RTT.

• #45 Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-016-0545-5

  MECP2 is a multifunctional protein which influences gene expression and metabolism on many levels. The main function of MECP2 is to recognize and bind specifically methylated cytosine residues in the DNA (namely 5MeCyt) that are enriched with A/T bases adjacent. Mutations in MECP2, especially in the MDB, which lead to loss of specific 5MeCyt binding functions are known to cause RTT. […] The molecular functions of MECP2 are known to influence various biological mechanisms, which are summarized and visualized in the pathway, namely 1) MECP2 influences global translation by enhancing the AKT/mTOR signaling pathway, 2) Alternative splicing of downstream gene products is affected because MECP2 forms a complex with YB1, an important splicing factor, 3) Expression of various microRNAs and long non-coding RNAs is regulated by MECP2, and 4) MECP2 triggers the chromatin compaction at methylated DNA sites which regulates the transcription of adjacent genes.

• #46 Solving the Mechanism of Rett Syndrome – Berkeley Lab – Berkeley Lab News Center

  https://newscenter.lbl.gov/2004/12/20/solving-the-mechanism-of-rett-syndrome/

  In MeCP2-knockout mouse brain, this silent chromatin was missing. […] In wild-type mice, they found that MeCP2 is required for the formation of a loop of silent chromatin between the Dlx5 and Dlx6 genes, by bringing together two sequences separated by more than 10,000 base pairs. […] Rett Syndrome symptoms can be associated with the failure of mutated MECP2 to regulate transcription of a specific gene, DLX5, one allele of which is normally imprinted. Without the MeCP2 protein, production of the Dlx5 protein is increased, which must influence production of the neurotransmitter GABA and may also affect the expression of other, related genes in the DLX family with consequences for the development of the brain. […] Absent or defective MeCP2 allows increased expression of the DLX5 gene through the loss of a loop of silent chromatin, and the activation of additional neighboring chromatin.

• #47 Solving the Mechanism of Rett Syndrome – Berkeley Lab – Berkeley Lab News Center

  https://newscenter.lbl.gov/2004/12/20/solving-the-mechanism-of-rett-syndrome/

  In MeCP2-knockout mouse brain, this silent chromatin was missing. […] In wild-type mice, they found that MeCP2 is required for the formation of a loop of silent chromatin between the Dlx5 and Dlx6 genes, by bringing together two sequences separated by more than 10,000 base pairs. […] Rett Syndrome symptoms can be associated with the failure of mutated MECP2 to regulate transcription of a specific gene, DLX5, one allele of which is normally imprinted. Without the MeCP2 protein, production of the Dlx5 protein is increased, which must influence production of the neurotransmitter GABA and may also affect the expression of other, related genes in the DLX family with consequences for the development of the brain. […] Absent or defective MeCP2 allows increased expression of the DLX5 gene through the loss of a loop of silent chromatin, and the activation of additional neighboring chromatin.

• #48

  https://cen.acs.org/biological-chemistry/epigenetics/Scientists-identify-possible-molecular-mechanism-Rett-syndrome/99/i24

  Researchers have found a new molecular role for MeCP2, the protein that doesnt work correctly in people with Rett syndrome. The findings could suggest new ways to treat the neurodevelopmental condition, the scientists say. […] Ali Hamiche at the Institute of Genetics and Molecular and Cellular Biology in Strasbourg and his group found the new role for MeCP2 while investigating methylated and hydroxymethylated cytosine and adenosine repeats in DNA (CACACACACA, and so on). The group was looking for proteins that bind or interact with these genetic elements to understand how these sequences affect gene regulation. […] The scientists found that when MeCP2 without Rett-related mutations binds to specific CA repeats, it changes the DNA structure. This change prevents DNA from being wrapped up into nucleosomes. In contrast, mutated MeCP2 proteins cant bind the CA repeats and, as a result, these repeat regions have many more nucleosomes and end up much more tightly packed. This tight packing could potentially change the regulation of genes along that stretch of DNA.

• #49 Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-016-0545-5

  MECP2 is a multifunctional protein which influences gene expression and metabolism on many levels. The main function of MECP2 is to recognize and bind specifically methylated cytosine residues in the DNA (namely 5MeCyt) that are enriched with A/T bases adjacent. Mutations in MECP2, especially in the MDB, which lead to loss of specific 5MeCyt binding functions are known to cause RTT. […] The molecular functions of MECP2 are known to influence various biological mechanisms, which are summarized and visualized in the pathway, namely 1) MECP2 influences global translation by enhancing the AKT/mTOR signaling pathway, 2) Alternative splicing of downstream gene products is affected because MECP2 forms a complex with YB1, an important splicing factor, 3) Expression of various microRNAs and long non-coding RNAs is regulated by MECP2, and 4) MECP2 triggers the chromatin compaction at methylated DNA sites which regulates the transcription of adjacent genes.

• #50 New Insight Into Rett Syndrome’s Disease Mechanisms | Technology Networks

  https://www.technologynetworks.com/genomics/news/new-aspect-of-rett-syndromes-pathogenesis-discovered-396420

  Researchers at the Josep Carreras Leukaemia Research Institute revealed a new aspect of Rett Syndromes pathogenesis that can lead to new therapeutical approaches in the future. […] According to the research by Dr. Edilene Siqueira and Dr. Snia Guil, loss of function of MeCP2 hallmark of the disease affects the long non-coding RNA NEAT1, promoting the malfunction of one of the cells maintenance systems. […] New research from the Regulatory RNA and Chromatin lab at the Josep Carreras Institute sheds light into one of these alterations: autophagy malfunction. […] In the research, first-authored by Dr. Edilene Siqueira and recently published in the longstanding scientific journal Nucleic Acids Research, the team used the latest genetic tools available, such as single-cell RNA sequencing and CRISPR/Cas9 gene editing technology, and found that mutations in MeCP2 led to the depletion of a long non-coding RNA called NEAT1.

• #51

  https://omim.org/entry/312750

  Marchetto et al. (2010) generated neurons with RTT-associated MECP2 mutations from induced pluripotent stem cells derived from fibroblasts isolated from patients with Rett syndrome. These cells were able to undergo X inactivation and generate functional neurons. Studies of these neurons in culture showed fewer synapses, reduced spine density, and small soma size compared to controls. In addition, these cells showed altered calcium signaling and electrophysiologic defects, particularly affecting glutamate signaling, compared to controls. The findings demonstrated that human RTT neurons have early developmental defects. Pharmacologic treatment of these cells with IGF1 (147440) and gentamicin, which causes read-through of nonsense mutations, showed some promising results. […] Muotri et al. (2010) showed that L1 neuronal transcription and retrotransposition in rodents are increased in the absence of Mecp2. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, they revealed that patients with Rett syndrome, carrying MeCP2 mutations, have increased susceptibility for L1 retrotransposition. Muotri et al. (2010) concluded that L1 retrotransposition can be controlled in a tissue-specific manner and that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition.

• #52 Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-016-0545-5

  MECP2 is a multifunctional protein which influences gene expression and metabolism on many levels. The main function of MECP2 is to recognize and bind specifically methylated cytosine residues in the DNA (namely 5MeCyt) that are enriched with A/T bases adjacent. Mutations in MECP2, especially in the MDB, which lead to loss of specific 5MeCyt binding functions are known to cause RTT. […] The molecular functions of MECP2 are known to influence various biological mechanisms, which are summarized and visualized in the pathway, namely 1) MECP2 influences global translation by enhancing the AKT/mTOR signaling pathway, 2) Alternative splicing of downstream gene products is affected because MECP2 forms a complex with YB1, an important splicing factor, 3) Expression of various microRNAs and long non-coding RNAs is regulated by MECP2, and 4) MECP2 triggers the chromatin compaction at methylated DNA sites which regulates the transcription of adjacent genes.

• #53

  https://omim.org/entry/312750

  Hendrich and Bickmore (2001) reviewed human disorders that share in common defects of chromatin structure or modification, including the ATR-X spectrum of disorders (301040), ICF syndrome (242860), Rett syndrome, Rubinstein-Taybi syndrome (180849), and Coffin-Lowry syndrome (303600). […] In rodent brain tissue, Deng et al. (2007) identified the FXYD1 (602359) promoter as an endogenous target of MECP2, which can cause transcriptional regulation of FXYD1. Transgenic Mecp2-null mice had increased Fxyd1 mRNA and protein levels in the frontal cortex, similar to that observed in patients with Rett syndrome. Increased Fxyd1 expression in Mecp2-null mice was associated with decreased Na,K-ATPase activity in the frontal cortex. In cultured mouse neurons, overexpression of Fxyd1 was associated with decreased neuronal dendritic tree and spine formation compared to controls, findings that have been observed in Rett syndrome. Overall, the results suggested that derepression of FXYD1, resulting from inactivation of MECP2, may contribute to the neuropathogenesis of Rett syndrome.

• #54 The Pathophysiology of Rett Syndrome With a Focus on Breathing Dysfunctions

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7864239/

  Rett syndrome (RTT), an X-chromosome-linked neurological disorder, is characterized by serious pathophysiology, including breathing and feeding dysfunctions, and alteration of cardiorespiratory coupling, a consequence of multiple interrelated disturbances in the genetic and homeostatic regulation of central and peripheral neuronal networks, redox state, and control of inflammation. Characteristic breath-holds, obstructive sleep apnea, and aerophagia result in intermittent hypoxia, which, combined with mitochondrial dysfunction, causes oxidative stressan important driver of the clinical presentation of RTT. […] The focus of this invited review article will be the girls with the classic phenotype, including our explanation of the altered physiology intrinsic to the condition and impacted by the recurrent intermittent hypoxemia due to the aberrant breathing.

• #55 The Pathophysiology of Rett Syndrome With a Focus on Breathing Dysfunctions

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7864239/

  Rett syndrome (RTT), an X-chromosome-linked neurological disorder, is characterized by serious pathophysiology, including breathing and feeding dysfunctions, and alteration of cardiorespiratory coupling, a consequence of multiple interrelated disturbances in the genetic and homeostatic regulation of central and peripheral neuronal networks, redox state, and control of inflammation. Characteristic breath-holds, obstructive sleep apnea, and aerophagia result in intermittent hypoxia, which, combined with mitochondrial dysfunction, causes oxidative stressan important driver of the clinical presentation of RTT. […] The focus of this invited review article will be the girls with the classic phenotype, including our explanation of the altered physiology intrinsic to the condition and impacted by the recurrent intermittent hypoxemia due to the aberrant breathing.

• #56 The Pathophysiology of Rett Syndrome With a Focus on Breathing Dysfunctions

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7864239/

  The astonishing reversal of neurological defects following the reactivation of Mecp2 expression in mice in which Mecp2 was silenced led to important insights. It illustrated that RTT is not a neurodegenerative disease and showed that homeostatic mechanisms are sufficiently powerful to reverse many of the imbalances and developmental processes that were severely affected by the mutation. […] However, homeostatic mechanisms are also powerful drivers of the clinical phenotype when MECP2 is mutated. […] The central mechanisms associated with these breathing alterations are thought to include increased excitability in respiratory areas like the pontine Klliker-Fuse nuclei (KF), the nucleus tractus solitarius (nTS), locus coeruleus, and ventrolateral medulla. […] The association of tonic HN with active expiration and post-inspiratory vagal activity is reminiscent of the breathhold activities seen in patients, and it is conceivable that related disturbances also contribute to loss of speech and impaired swallowing.

• #57 The Pathophysiology of Rett Syndrome With a Focus on Breathing Dysfunctions

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7864239/

  Insights into the mechanisms underlying these breathing abnormalities were gained by studying Mecp2 global and targeted knockout (KO) mice. These mice show respiratory irregularities with frequent periods of prolonged respiratory cycles that are reminiscent of breathholds in RTT patients. […] The episodic appearance of breathholds triggers a cascade of other events that will inevitably lead to intermittent hypoxia. […] Intermittent hypoxia leads to disturbances in sympathetic and parasympathetic control, which likely contributes to the dysautonomia characteristic of RTT. […] The effects of intermittent hypoxia are largely mediated by reactive oxygen species (ROS) and oxidative stress, which is further aggravated in RTT because of altered mitochondrial structure and enzyme activity.

• #58 The Pathophysiology of Rett Syndrome With a Focus on Breathing Dysfunctions

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7864239/

  Insights into the mechanisms underlying these breathing abnormalities were gained by studying Mecp2 global and targeted knockout (KO) mice. These mice show respiratory irregularities with frequent periods of prolonged respiratory cycles that are reminiscent of breathholds in RTT patients. […] The episodic appearance of breathholds triggers a cascade of other events that will inevitably lead to intermittent hypoxia. […] Intermittent hypoxia leads to disturbances in sympathetic and parasympathetic control, which likely contributes to the dysautonomia characteristic of RTT. […] The effects of intermittent hypoxia are largely mediated by reactive oxygen species (ROS) and oxidative stress, which is further aggravated in RTT because of altered mitochondrial structure and enzyme activity.

• #59 The Pathophysiology of Rett Syndrome With a Focus on Breathing Dysfunctions

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7864239/

  Insights into the mechanisms underlying these breathing abnormalities were gained by studying Mecp2 global and targeted knockout (KO) mice. These mice show respiratory irregularities with frequent periods of prolonged respiratory cycles that are reminiscent of breathholds in RTT patients. […] The episodic appearance of breathholds triggers a cascade of other events that will inevitably lead to intermittent hypoxia. […] Intermittent hypoxia leads to disturbances in sympathetic and parasympathetic control, which likely contributes to the dysautonomia characteristic of RTT. […] The effects of intermittent hypoxia are largely mediated by reactive oxygen species (ROS) and oxidative stress, which is further aggravated in RTT because of altered mitochondrial structure and enzyme activity.

• #60 Pathogenesis of Lethal Aspiration Pneumonia in Mecp2-null Mouse Model for Rett Syndrome | Scientific Reports

  https://www.nature.com/articles/s41598-017-12293-8

  Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in the gene encoding the transcriptional regulator Methyl-CpG-binding protein 2 (MeCP2), located on the X chromosome. […] Previous studies showed that MeCP2 is highly expressed in the lung, but its role in pulmonary function remains unknown. In this study, we found that MeCP2 deficiency affects pulmonary gene expression and structures. […] These results indicated that aspiration might be a cause of inflammatory lung injury in Mecp2-null mice. […] On the other hand, MeCP2 deficiency affected the expression of several neuromodulator genes in the lower brainstem. […] These findings suggest that alteration of SP expression in brainstem may be involved in autonomic dysregulation, and may be one of the causes of aspiration in Mecp2-null mice.

• #61 Pathogenesis of Lethal Aspiration Pneumonia in Mecp2-null Mouse Model for Rett Syndrome | Scientific Reports

  https://www.nature.com/articles/s41598-017-12293-8

  In this study, we investigated developmental mechanisms of inflammatory lung injury and examined the effects of MeCP2 deficiency in the respiratory system itself. Our results demonstrate that MeCP2 deficiency affects pulmonary gene expression and lung structures. In addition, aspiration pneumonia might be a cause of inflammatory lung injury in the Mecp2-null mouse model of RTT. […] These results indicate that lung abnormalities in Mecp2-null mice occurred in specific pulmonary lobes. […] These results indicate that the inflammatory lung injury in Mecp2-null mice is induced by aspiration. […] These findings suggest that disturbances in various neurotransmitter systems of the lower brainstem may lead to aspiration in Mecp2-null mice. […] These results indicate that MeCP2 deficiency affects the expression/distribution of SP in the lower brainstem of autonomic control centers. These findings also suggest that alteration of SP expression/distribution in the brainstem may lead to dysfunction of autonomic systems, leading to aspiration, in Mecp2-null mice.

• #62 Rett syndrome: insights into genetic, molecular and circuit mechanisms | Nature Reviews Neuroscience

  https://www.nature.com/articles/s41583-018-0006-3

  Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). […] Here, we review recent advances in understanding how loss of MeCP2 impacts different stages of brain development, discuss recent findings demonstrating the molecular role of MeCP2 as a transcriptional repressor, assess primary and secondary effects of MeCP2 loss and examine how loss of MeCP2 can result in an imbalance of neuronal excitation and inhibition at the circuit level along with dysregulation of activity-dependent mechanisms. […] These factors present challenges to the search for mechanism-based therapeutics for RTT and suggest specific approaches that may be more effective than others. […] This study shows that mice with Mecp2 deleted only in GABAergic neurons recapitulate many of the deficits observed in global knockout mice, suggesting that MeCP2 is crucial for the normal function of GABAergic neurons and that the dysfunction of GABAergic neurons contributes to RTT phenotypes.

• #63 Rett Syndrome: Practice Essentials, Background, Pathophysiology and Etiology

  https://emedicine.medscape.com/article/916377-overview

  Areas of research have included the study of insulinlike growth factor 1 (IGF-1), which may extend the life span and increase brain weight in mice with RS. In addition, IGF-1 may correct the deficit in brain synaptic maturation and reverse the reduction of PSD-95 in the motor cortex. […] Scoliosis may be associated with mutation or deletion of p.Arg255.

• #64 Trofinetide Mechanism of Action to Treat Rett Syndrome | CheckRare

  https://checkrare.com/trofinetide-mechanism-of-action-to-treat-rett-syndrome/

  Rett syndrome is a rare progressive neurodevelopmental condition that primarily affects girls. […] As Dr. Bishop explains, trofinetide is a synthetic analog of the aminoterminal tripeptide of IGF-1. It is designed to treat the core symptoms of Rett syndrome by potentially reducing neuroinflammation and supporting synaptic function. Trofinetide is thought to stimulate synaptic maturation and overcome the synaptic and neuronal immaturities that are characteristic of Rett syndrome pathophysiology. […] In the central nervous system, IGF-1 is produced by both neurons and glia, and is critical for both normal development and for response to injury and disease.

• #65 Trofinetide Proposed Mechanism of Action in Rett Syndrome | CheckRare

  https://checkrare.com/trofinetide-proposed-mechanism-of-action-in-rett-syndrome/

  Rett syndrome is a rare progressive neurodevelopmental condition that primarily affects girls. […] Trofinetide is designed to treat the core symptoms of Rett syndrome by potentially reducing neuroinflammation and supporting synaptic function. Trofinetide is thought to stimulate synaptic maturation and overcome the synaptic and neuronal immaturities that are characteristic of Rett syndrome pathophysiology. […] In the central nervous system, IGF-1 is produced by both neurons and glia, and is critical for both normal development and for response to injury and disease.

• #66 Rett syndrome: insights into genetic, molecular and circuit mechanisms | Nature Reviews Neuroscience

  https://www.nature.com/articles/s41583-018-0006-3

  This paper shows that expression of MeCP2 exclusively in astrocytes rescues some of the major deficits in MeCP2-deficient mice, suggesting that MeCP2 does not function only in neurons and has non-cell-autonomous effects. […] This study shows that systemic treatment of MeCP2-mutant mice with a truncated form of IGF1 restores excitatory synapses and improves neurological deficits. […] This study demonstrates that MeCP2 binds to mCA sites and this binding represses the expression of long genes. […] This study identifies the NID in MeCP2 and demonstrates that RTT-causing mutations in the NID abolish the interaction between MeCP2 and the NCoRSMRT co-repressor complexes. […] This study demonstrates that site-directed RNA editing is able to repair, at the mRNA level, a RTT-causing mutation affecting the mouse MeCP2 MBD.

• #67 The Pathophysiology of Rett Syndrome With a Focus on Breathing Dysfunctions

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7864239/

  The astonishing reversal of neurological defects following the reactivation of Mecp2 expression in mice in which Mecp2 was silenced led to important insights. It illustrated that RTT is not a neurodegenerative disease and showed that homeostatic mechanisms are sufficiently powerful to reverse many of the imbalances and developmental processes that were severely affected by the mutation. […] However, homeostatic mechanisms are also powerful drivers of the clinical phenotype when MECP2 is mutated. […] The central mechanisms associated with these breathing alterations are thought to include increased excitability in respiratory areas like the pontine Klliker-Fuse nuclei (KF), the nucleus tractus solitarius (nTS), locus coeruleus, and ventrolateral medulla. […] The association of tonic HN with active expiration and post-inspiratory vagal activity is reminiscent of the breathhold activities seen in patients, and it is conceivable that related disturbances also contribute to loss of speech and impaired swallowing.

• #68 Rett syndrome: insights into genetic, molecular and circuit mechanisms | Nature Reviews Neuroscience

  https://www.nature.com/articles/s41583-018-0006-3

  This paper shows that expression of MeCP2 exclusively in astrocytes rescues some of the major deficits in MeCP2-deficient mice, suggesting that MeCP2 does not function only in neurons and has non-cell-autonomous effects. […] This study shows that systemic treatment of MeCP2-mutant mice with a truncated form of IGF1 restores excitatory synapses and improves neurological deficits. […] This study demonstrates that MeCP2 binds to mCA sites and this binding represses the expression of long genes. […] This study identifies the NID in MeCP2 and demonstrates that RTT-causing mutations in the NID abolish the interaction between MeCP2 and the NCoRSMRT co-repressor complexes. […] This study demonstrates that site-directed RNA editing is able to repair, at the mRNA level, a RTT-causing mutation affecting the mouse MeCP2 MBD.

• #69 Rett syndrome: insights into genetic, molecular and circuit mechanisms | Nature Reviews Neuroscience

  https://www.nature.com/articles/s41583-018-0006-3

  This paper shows that expression of MeCP2 exclusively in astrocytes rescues some of the major deficits in MeCP2-deficient mice, suggesting that MeCP2 does not function only in neurons and has non-cell-autonomous effects. […] This study shows that systemic treatment of MeCP2-mutant mice with a truncated form of IGF1 restores excitatory synapses and improves neurological deficits. […] This study demonstrates that MeCP2 binds to mCA sites and this binding represses the expression of long genes. […] This study identifies the NID in MeCP2 and demonstrates that RTT-causing mutations in the NID abolish the interaction between MeCP2 and the NCoRSMRT co-repressor complexes. […] This study demonstrates that site-directed RNA editing is able to repair, at the mRNA level, a RTT-causing mutation affecting the mouse MeCP2 MBD.

• #70 A step closer to understanding Rett syndrome

  https://www.carrerasresearch.org/en/news/a-step-closer-to-understanding-rett-syndrome

  In the research, first-authored by Dr. Edilene Siqueira and recently published in the longstanding scientific journal Nucleic Acids Research, the team used the latest genetic tools available, such as single-cell RNA sequencing and CRISPR/Cas9 gene editing technology, and found that mutations in MeCP2 led to the depletion of a long non-coding RNA called NEAT1. As it turns out, NEAT1 controls the autophagy system by establishing direct RNA-RNA contacts with components of its machinery and directing their localization within the cell. Consequently, NEAT1 deficiency contributes to some of the cellular alterations found in Rett syndrome. […] Furthermore, the team demonstrated that restoring NEAT1 could reverse these alterations in in vitro models of the disease, opening the door to the exploration of new therapeutic approaches in the coming years.

• #71 Understanding the Mechanisms of Stress Related Pathways in Rett Syndrome

  https://escholarship.org/uc/item/5wz4d185

  Rett syndrome is a severe neurodevelopmental disorder that arises due to a mutation in methyl-CpG-binding protein 2 (MECP2). […] The mechanism underlying the onset of Rett syndrome remains poorly understood. We used Rett patient derived human induced pluripotent stem cells (hiPSCs) to model Rett syndrome in vitro in an attempt to elucidate the pathways implicated in Rett phenotype. […] We discovered that Rett neurons undergo neuronal stress resulting in an increased expression of OCT1 and P53 target genes. In addition, mutant neurons exhibit premature senescence accompanied by elevated levels of DNA damage. […] We discovered that lack of MECP2 leads to misregulated synaptic genes as well as abnormal metabolism. […] We confirmed faulty metabolism and mitochondrial respiration in our in vitro model, and showed that various types of neuronal stress lead to induction of OCT1 in vitro.

• #72 Understanding the Mechanisms of Stress Related Pathways in Rett Syndrome

  https://escholarship.org/uc/item/5wz4d185

  Rett syndrome is a severe neurodevelopmental disorder that arises due to a mutation in methyl-CpG-binding protein 2 (MECP2). […] The mechanism underlying the onset of Rett syndrome remains poorly understood. We used Rett patient derived human induced pluripotent stem cells (hiPSCs) to model Rett syndrome in vitro in an attempt to elucidate the pathways implicated in Rett phenotype. […] We discovered that Rett neurons undergo neuronal stress resulting in an increased expression of OCT1 and P53 target genes. In addition, mutant neurons exhibit premature senescence accompanied by elevated levels of DNA damage. […] We discovered that lack of MECP2 leads to misregulated synaptic genes as well as abnormal metabolism. […] We confirmed faulty metabolism and mitochondrial respiration in our in vitro model, and showed that various types of neuronal stress lead to induction of OCT1 in vitro.

• #73 Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-016-0545-5

  The examination and investigation of RTT females (and model systems) revealed that an impaired MECP2 influences biological pathways on many levels. Several genes have been found to be increased or decreased in expression, levels of various metabolites are changed and several biological pathways were found to be typically affected although the molecular mechanisms are not yet clear. […] Bedogni et al. mentioned the difficulty to identify unique target pathways of MECP2 because MECP2 is both a repressor and an activator of transcription and the balancing and timing of transcription levels seems to contribute more to disorder development than activation of single pathways. […] In summary, MECP2 affects epigenetic regulation of gene expression, which changes neurobiological activity, network formation and function which causes the major phenotype.

• #74 Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-016-0545-5

  The examination and investigation of RTT females (and model systems) revealed that an impaired MECP2 influences biological pathways on many levels. Several genes have been found to be increased or decreased in expression, levels of various metabolites are changed and several biological pathways were found to be typically affected although the molecular mechanisms are not yet clear. […] Bedogni et al. mentioned the difficulty to identify unique target pathways of MECP2 because MECP2 is both a repressor and an activator of transcription and the balancing and timing of transcription levels seems to contribute more to disorder development than activation of single pathways. […] In summary, MECP2 affects epigenetic regulation of gene expression, which changes neurobiological activity, network formation and function which causes the major phenotype.

• #75 Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-016-0545-5

  The examination and investigation of RTT females (and model systems) revealed that an impaired MECP2 influences biological pathways on many levels. Several genes have been found to be increased or decreased in expression, levels of various metabolites are changed and several biological pathways were found to be typically affected although the molecular mechanisms are not yet clear. […] Bedogni et al. mentioned the difficulty to identify unique target pathways of MECP2 because MECP2 is both a repressor and an activator of transcription and the balancing and timing of transcription levels seems to contribute more to disorder development than activation of single pathways. […] In summary, MECP2 affects epigenetic regulation of gene expression, which changes neurobiological activity, network formation and function which causes the major phenotype.

• #76

  https://www.deanfrancispress.com/index.php/ms/article/view/579

  Rett Syndrome is a neurological condition primarily affecting women. Several gene mutations have been discovered to play a role in this disease, with the MeCP2 mutation being the most widely known and frequent cause. However, the mechanism behind how MeCP2 affects the human brain on a molecular level remains to be discovered. […] Future studies could revolve around the root causes of Rett Syndrome, such as the lack of MeCP2 in neurons, and attempt to solve the problem fundamentally.

• #77 Mechanisms and therapeutics for Rett Syndrome – SUR LAB

  https://www.surlab.org/mechanisms-and-therapeutics-for-rett-syndrome/

  MeCP2 is an epigenetic modulator of gene expression that has recently been shown to interact significantly with microRNA machinery. Multiple lines of evidence point to a role for MeCP2 in successive stages of brain development, including prenatal neurogenesis, postnatal development of connections and function, and experience-dependent synaptic plasticity. […] We hypothesize that the pleiotropic effects of MeCP2 are mediated in prenatal development via a set of early regulated miRNAs that influence neurogenesis; during postnatal development through a different set of miRNAs that regulate Insulin-like growth factor 1 (IGF1) signaling; and in late development into adulthood via a third set of miRNAs that influence synaptic function and plasticity. […] An important goal is to discover novel therapeutics that target fundamental mechanisms of MeCP2 function.

• #78 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20241219/New-molecular-insights-into-the-early-stages-of-Rett-syndrome.aspx

  Scientists investigating the severe developmental disorder known as Rett syndrome have discovered a series of crucial molecular changes that occur long before symptoms appear. […] That investigation has revealed a whole „cascade” of molecular changes that fundamentally alter how genes work in brain cells. […] The discovery of these molecular changes and the specific mechanisms responsible for the changes sheds much-needed light on the development of Rett syndrome. […] Our study uncovered a core set of genes that are disrupted very early on before any overt symptoms have presented. […] „We discovered several candidate biomarkers sensitive to MECP2 levels that could be the key to developing safe gene therapies for Rett,” he said.

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