Methyl-CpG-binding protein 2 mediates overlapping mechanisms across brain disorders

AbstractMECP2 and its product, Methyl-CpG binding protein 2 (MeCP2), are mostly known for their association to Rett Syndrome (RTT), a rare neurodevelopmental disorder. Additional evidence suggests that MECP2 may underlie other neuropsychiatric and neurological conditions, and perhaps modulate common presentations and pathophysiology across disorders. To clarify the mechanisms of these interactions, we develop a method that uses the binding properties of MeCP2 to identify its targets, and in particular, the genes recognized by MeCP2 and associated to several neurological and neuropsychiatric disorders. Analysing mechanisms and pathways modulated by these genes, we find that they are involved in three main processes: neuronal transmission, immuno-reactivity, and development. Also, while the nervous system is the most relevant in the pathophysiology of the disorders, additional systems may contribute to MeCP2 action through its target genes. We tested our results with transcriptome analysis on Mecp2-null models and cells derived from a patient with RTT, confirming that the genes identified by our procedure are directly modulated by MeCP2. Thus, MeCP2 may modulate similar mechanisms in different pathologies, suggesting that treatments for one condition may be effective for related disorders.

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Methyl-CpG2-binding protein 2 mediates overlapping mechanisms across brain disorders

10.1101/819573 ◽

2019 ◽

Author(s):

Snow Bach ◽

Niamh M. Ryan ◽

Paolo Guasoni ◽

Aiden Corvin ◽

Daniela Tropea

Keyword(s):

Target Genes ◽

Binding Protein ◽

Brain Disorders ◽

Chromatin Binding ◽

Binding Properties ◽

Hyperactivity Disorder ◽

Potential Applications ◽

Neuronal Transmission ◽

Neuropsychiatric Conditions ◽

Common Molecular Basis

AbstractMethyl-CpG binding protein 2 (MeCP2) is a chromatin-binding protein and a modulator of gene expression. Initially identified as an oncogene, MECP2 is now mostly associated to Rett Syndrome, a neurodevelopmental condition, though there is evidence of its influence in other brain disorders.We design a procedure that considers several binding properties of MeCP2 and we screen for potential targets across neurological and neuropsychiatric conditions.We find MeCP2 target genes associated to a range of disorders, including - among others-Alzheimer Disease, Autism, Attention Deficit Hyperactivity Disorder and Multiple Sclerosis. The analysis of biological mechanisms and pathways modulated by MeCP2’s target genes shows that such mechanisms are involved in three main processes: neuronal transmission, immuno-reactivity and development.These results suggest that similar symptoms present in different pathologies have a common molecular basis, and that treatments for one condition have potential applications to related disorders.

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Persistent Unresolved Inflammation in the Mecp2-308 Female Mutated Mouse Model of Rett Syndrome

Mediators of Inflammation ◽

10.1155/2017/9467819 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 11

Author(s):

Alessio Cortelazzo ◽

Claudio De Felice ◽

Bianca De Filippis ◽

Laura Ricceri ◽

Giovanni Laviola ◽

...

Keyword(s):

Mouse Model ◽

Rett Syndrome ◽

Binding Protein ◽

Neurodevelopmental Disorder ◽

Unknown Origin ◽

Apolipoprotein A1 ◽

Inflammatory Status ◽

Truncating Mutation ◽

Alpha 1 Antitrypsin ◽

First Time

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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Rescue of Methyl-CpG Binding Protein 2 Dysfunction-induced Defects in Newborn Neurons by Pentobarbital

Neurotherapeutics ◽

10.1007/s13311-015-0343-0 ◽

2015 ◽

Vol 12 (2) ◽

pp. 477-490 ◽

Cited By ~ 12

Author(s):

Dongliang Ma ◽

Su-In Yoon ◽

Chih-Hao Yang ◽

Guillaume Marcy ◽

Na Zhao ◽

...

Keyword(s):

Rett Syndrome ◽

Hippocampal Neurons ◽

Granule Cells ◽

Binding Protein ◽

Neurodevelopmental Disorder ◽

Network Activity ◽

Aminobutyric Acid ◽

Structural Defects

Abstract Rett syndrome is a neurodevelopmental disorder that usually arises from mutations or deletions in methyl-CpG binding protein 2 (MeCP2), a transcriptional regulator that affects neuronal development and maturation without causing cell loss. Here, we show that silencing of MeCP2 decreased neurite arborization and synaptogenesis in cultured hippocampal neurons from rat fetal brains. These structural defects were associated with alterations in synaptic transmission and neural network activity. Similar retardation of dendritic growth was also observed in MeCP2-deficient newborn granule cells in the dentate gyrus of adult mouse brains in vivo, demonstrating direct and cell-autonomous effects on individual neurons. These defects, caused by MeCP2 deficiency, were reversed by treatment with the US Food and Drug Administration-approved drug, pentobarbital, in vitro and in vivo, possibly caused by modulation of γ-aminobutyric acid signaling. The results indicate that drugs modulating γ-aminobutyric acid signaling are potential therapeutics for Rett syndrome.

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Molecular Context-Dependent Effects Induced by Rett Syndrome-Associated Mutations in MeCP2

Biomolecules ◽

10.3390/biom10111533 ◽

2020 ◽

Vol 10 (11) ◽

pp. 1533 ◽

Cited By ~ 1

Author(s):

David Ortega-Alarcon ◽

Rafael Claveria-Gimeno ◽

Sonia Vega ◽

Olga C. Jorge-Torres ◽

Manel Esteller ◽

...

Keyword(s):

Rett Syndrome ◽

Neuronal Development ◽

Binding Protein ◽

Neurodevelopmental Disorder ◽

Intrinsically Disordered Protein ◽

Loss Of Function ◽

Intrinsically Disordered ◽

Biophysical Study ◽

Molecular Context ◽

Functional Features

Methyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator and a chromatin-binding protein involved in neuronal development and maturation. Loss-of-function mutations in MeCP2 result in Rett syndrome (RTT), a neurodevelopmental disorder that is the main cause of mental retardation in females. MeCP2 is an intrinsically disordered protein (IDP) constituted by six domains. Two domains are the main responsible elements for DNA binding (methyl-CpG binding domain, MBD) and recruitment of gene transcription/silencing machinery (transcription repressor domain, TRD). These two domains concentrate most of the RTT-associated mutations. R106W and R133C are associated with severe and mild RTT phenotype, respectively. We have performed a comprehensive characterization of the structural and functional impact of these substitutions at molecular level. Because we have previously shown that the MBD-flanking disordered domains (N-terminal domain, NTD, and intervening domain, ID) exert a considerable influence on the structural and functional features of the MBD (Claveria-Gimeno, R. et al. Sci Rep. 2017, 7, 41635), here we report the biophysical study of the influence of the protein scaffold on the structural and functional effect induced by these two RTT-associated mutations. These results represent an example of how a given mutation may show different effects (sometimes opposing effects) depending on the molecular context.

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Cell cloning-based transcriptome analysis in Rett patients: relevance to the pathogenesis of Rett syndrome of new human MeCP2 target genes

Journal of Cellular and Molecular Medicine ◽

10.1111/j.1582-4934.2010.01107.x ◽

2010 ◽

Vol 14 (7) ◽

pp. 1962-1974 ◽

Cited By ~ 23

Author(s):

J. Nectoux ◽

Y. Fichou ◽

H. Rosas-Vargas ◽

N. Cagnard ◽

N. Bahi-Buisson ◽

...

Keyword(s):

Rett Syndrome ◽

Transcriptome Analysis ◽

Target Genes ◽

Cell Cloning

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A Novel Methyl-CpG Binding Protein 2 (MECP2) Variant in an Indian Girl with Rett Syndrome

JOURNAL FOR CLINICAL AND DIAGNOSTIC RESEARCH ◽

10.7860/jcdr/2020/47641.14753 ◽

2021 ◽

Author(s):

Pratiksha Chheda ◽

Shailesh Pande ◽

Tavisha Dama ◽

Dollar Goradia ◽

Sushant Vinarkar

Keyword(s):

Rett Syndrome ◽

De Novo ◽

Binding Protein ◽

Neurodevelopmental Disorder ◽

Missense Variant ◽

Clinical Findings ◽

Indian Girl ◽

Gene Coding ◽

Gradual Loss ◽

Repetitive Movements

Rett syndrome is an X-linked dominant disorder that is primarily seen in females and is linked to mutations in the gene coding for Methyl-CpG Binding Protein 2 (MECP2). It is a neurodevelopmental disorder characterised by impairments in language, repetitive movements, early-onset seizures, delayed growth, autistic features, intellectual disability and abnormal Electroencephalograms (EEG). Author’s reported a case of three year six months old Indian girl who was born of a nonconsanguineous marriage presented with stereotypic hand movements, gradual loss of speech, inability to walk independently and frequent episodes of seizure. Genetic testing for analysis of MECP2 mutations was performed and a novel de novo missense variant (c.361G>A, p.Asp121Asn) was identified, which was predicted to be disease causing on the basis of insilico analysis and clinical findings. The study suggested that a careful evaluation of the pathogenic nature of MECP2 variants supports clinical diagnosis and aids in genetic counseling and patient management.

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Reconsidering NMIHBA Core Features: Macrocephaly Is Not a So Unusual Sign in PRUNE1-Related Encephalopathy

Journal of Pediatric Neurology ◽

10.1055/s-0040-1715526 ◽

2020 ◽

Author(s):

Roberta Battini ◽

Enrico Bertini ◽

Roberta Milone ◽

Chiara Aiello ◽

Rosa Pasquariello ◽

...

Keyword(s):

Nervous System ◽

Differential Diagnosis ◽

Clinical Features ◽

Neurodevelopmental Disorder ◽

Recurrent Mutation ◽

Clinical Suspicion ◽

Alexander Disease ◽

Brain Anomalies ◽

Progressive Encephalopathy ◽

Core Features

Abstract PRUNE1-related disorders manifest as severe neurodevelopmental conditions associated with neurodegeneration, implying a differential diagnosis at birth with static encephalopathies, and later with those manifesting progressive brain damage with the involvement of both the central and the peripheral nervous system.Here we report on another patient with PRUNE1 (p.Asp106Asn) recurrent mutation, whose leukodystrophy, inferior olives hyperintensity, and macrocephaly led to the misleading clinical suspicion of Alexander disease. Clinical features, together with other recent descriptions, suggest avoiding the term “microcephaly” in defining this disorder that could be renamed “neurodevelopmental disorder with progressive encephalopathy, hypotonia, and variable brain anomalies” (NPEHBA).

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