scholarly journals Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease

Biomolecules ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 75
Author(s):  
Shervin Pejhan ◽  
Mojgan Rastegar
Keyword(s):  
Rett Syndrome ◽  
Binding Protein ◽  
Autism Spectrum ◽  
Cellular Systems ◽  
De Novo Mutation ◽  
Genetic Mutations ◽  
Mecp2 Gene ◽  
Altered Expression ◽  
The Brain

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. While the majority of RTT patients have MECP2 mutations (classical RTT), a small fraction of the patients (atypical RTT) may carry genetic mutations in other genes such as the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1. Due to the neurological basis of RTT symptoms, MeCP2 function was originally studied in nerve cells (neurons). However, later research highlighted its importance in other cell types of the brain including glia. In this regard, scientists benefitted from modeling the disease using many different cellular systems and transgenic mice with loss- or gain-of-function mutations. Additionally, limited research in human postmortem brain tissues provided invaluable findings in RTT pathobiology and disease mechanism. MeCP2 expression in the brain is tightly regulated, and its altered expression leads to abnormal brain function, implicating MeCP2 in some cases of autism spectrum disorders. In certain disease conditions, MeCP2 homeostasis control is impaired, the regulation of which in rodents involves a regulatory microRNA (miR132) and brain-derived neurotrophic factor (BDNF). Here, we will provide an overview of recent advances in understanding the underlying mechanism of disease in RTT and the associated genetic mutations in the MECP2 gene along with the pathobiology of the disease, the role of the two most studied protein variants (MeCP2E1 and MeCP2E2 isoforms), and the regulatory mechanisms that control MeCP2 homeostasis network in the brain, including BDNF and miR132.

The methyl-CpG-binding protein MeCP2 and neurological disease

2008 ◽  
Vol 36 (4) ◽  
pp. 575-583 ◽  
Author(s):  
Adrian Bird
Keyword(s):  
Dna Methylation ◽  
Rett Syndrome ◽  
Dna Sequences ◽  
Neurological Disease ◽  
Binding Protein ◽  
Autism Spectrum ◽  
Model Systems ◽  
Mecp2 Gene ◽  
Methylated Dna ◽  
Protein Mecp2

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

scholarly journals FOXP1 syndrome: a review of the literature and practice parameters for medical assessment and monitoring

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Reymundo Lozano ◽  
Catherine Gbekie ◽  
Paige M. Siper ◽  
Shubhika Srivastava ◽  
Jeffrey M. Saland ◽  
...  
Keyword(s):  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Medical Assessment ◽  
Forkhead Box ◽  
Organ Systems ◽  
Practice Parameters ◽  
Assessment And Monitoring ◽  
Multidisciplinary Group ◽  
The Brain

AbstractFOXP1 syndrome is a neurodevelopmental disorder caused by mutations or deletions that disrupt the forkhead box protein 1 (FOXP1) gene, which encodes a transcription factor important for the early development of many organ systems, including the brain. Numerous clinical studies have elucidated the role of FOXP1 in neurodevelopment and have characterized a phenotype. FOXP1 syndrome is associated with intellectual disability, language deficits, autism spectrum disorder, hypotonia, and congenital anomalies, including mild dysmorphic features, and brain, cardiac, and urogenital abnormalities. Here, we present a review of human studies summarizing the clinical features of individuals with FOXP1 syndrome and enlist a multidisciplinary group of clinicians (pediatrics, genetics, psychiatry, neurology, cardiology, endocrinology, nephrology, and psychology) to provide recommendations for the assessment of FOXP1 syndrome.

ChemInform Abstract: Role of Heart-Type Fatty Acid Binding Protein in the Brain Function

ChemInform ◽  
2009 ◽  
Vol 40 (26) ◽  
Author(s):  
Keiju Motohashi ◽  
Yui Yamamoto ◽  
Norifumi Shioda ◽  
Hisatake Kondo ◽  
Yuji Owada ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Brain Function ◽  
Fatty Acid Binding Protein ◽  
Binding Protein ◽  
Fatty Acid Binding ◽  
Acid Binding Protein ◽  
The Brain

scholarly journals The Role of Iron in the Pathogenesis of Autism Spectrum Disorders in Children

2018 ◽  
Vol 17 (4) ◽  
pp. 281-286 ◽  
Author(s):  
Olga V. Kostina
Keyword(s):  
Autism Spectrum Disorders ◽  
Iron Metabolism ◽  
Biochemical Parameters ◽  
Children With Autism ◽  
Neuropsychiatric Disorders ◽  
Perinatal Period ◽  
Autism Spectrum ◽  
Spectrum Disorders ◽  
The Brain

The review presents an analysis of the mechanisms of iron effect on the brain development. The importance of iron deficiency in the perinatal period is considered as a risk factor for the development of neuropsychiatric disorders in children with autism spectrum disorders (ASDs). Possible causes of sideropenia are discussed; data on haematological and biochemical parameters characterizing iron metabolism in children with ASDs are presented. The demand for studying the role of iron metabolism imbalance in the development of neuropsychiatric disorders in order to clarify pathogenetic mechanisms of ASDs and to determine methods for their correction is emphasized.

scholarly journals Language impairments in ASD resulting from a failed domestication of the human brain

2016 ◽  
Author(s):  
Antonio Benítez-Burraco ◽  
Wanda Lattanzi ◽  
Elliot Murphy
Keyword(s):  
Human Brain ◽  
Neural Crest ◽  
Language Processing ◽  
Expression Profiles ◽  
Autism Spectrum ◽  
Human Populations ◽  
Altered Expression ◽  
Domestication Syndrome ◽  
High Prevalence ◽  
The Brain

AbstractAutism spectrum disorders (ASD) are pervasive neurodevelopmental disorders entailing social and cognitive deficits, including marked problems with language. Numerous genes have been associated with ASD, but it is unclear how language deficits arise from gene mutation or dysregulation. It is also unclear why ASD shows such high prevalence within human populations. Interestingly, the emergence of a modern faculty of language has been hypothesised to be linked to changes in the human brain/skull, but also to the process of self-domestication of the human species. It is our intention to show that people with ASD exhibit less marked domesticated traits at the morphological, physiological, and behavioural levels. We also discuss many ASD candidates represented among the genes known to be involved in the domestication syndrome (the constellation of traits exhibited by domesticated mammals, which seemingly results from the hypofunction of the neural crest) and among the set of genes involved in language function closely connected to them. Moreover, many of these genes show altered expression profiles in the brain of autists. In addition, some candidates for domestication and language-readiness show the same expression profile in people with ASD and chimps in different brain areas involved in language processing. Similarities regarding the brain oscillatory behaviour of these areas can be expected too. We conclude that ASD may represent an abnormal ontogenetic itinerary for the human faculty of language resulting in part from changes in genes important for the domestication syndrome and, ultimately, from the normal functioning of the neural crest.

scholarly journals A Case Study on Management of Rett Syndrome by Wholistic approach

2020 ◽  
Vol 11 (2) ◽  
pp. 351-357
Author(s):  
Renu Rathi ◽  
Bharat Rathi ◽  
Rakesh Khatana ◽  
Suraj Sankh
Keyword(s):  
Case Report ◽  
Rett Syndrome ◽  
Motor Development ◽  
Autism Spectrum ◽  
Severe Form ◽  
Fine Motor ◽  
Gross Motor ◽  
Gross Motor Development

Background: Rett syndrome-RS comes under Autism spectrum disorder-ASD which is a neurodevelopmental syndrome. It is diagnosed by the main differentiating features of lack of interpersonal and communication skills, poor eye contact, delayed speech with pervasive abnormal body movements. Aim and Objectives: This case report is aimed at dissemination of comprehensive role of Ayurveda in management of ASD, Rett syndrome. Material and Methods: RS is the severe form of ASD. This case study of 2.3 year’s girl presented with RS and global delay, being treated with wholistic approach. It comprises Ayurveda chikitsa and other therapies like Yoga, hydrotherapy, occupational, music, physiotherapy and many more. Observation and Result: Patient has shown promising results in all developmental milestones such as gross motor, fine motor and personal social in 6 months duration except language. Different varieties of massage therapy, diet and Basti, Nasya (Panchkarma) procedures, Omkar mantra chanting, passive Yogasana were done. Conclusion: In this case report, mainly Ayurveda interventions were implemented with wholistic approach as an adjuvant, received good result in gross motor development which is very difficult in RS, hence it is a unique case. It also opened the door of wholistic approach with the hope to deliver the good result in similar disorders.

The epigenetic regulation of synaptic genes contributes to the etiology of autism

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Annamaria Srancikova ◽  
Zuzana Bacova ◽  
Jan Bakos
Keyword(s):  
Epigenetic Regulation ◽  
Neurodevelopmental Disorders ◽  
Autism Spectrum ◽  
Prader Willi Syndrome ◽  
Epigenetic Mechanisms ◽  
Substantial Evidence ◽  
Autistic Symptoms ◽  
Spectrum Disorders ◽  
The Brain

Abstract Epigenetic mechanisms greatly affect the developing brain, as well as the maturation of synapses with pervasive, long-lasting consequences on behavior in adults. Substantial evidence exists that implicates dysregulation of epigenetic mechanisms in the etiology of neurodevelopmental disorders. Therefore, this review explains the role of enzymes involved in DNA methylation and demethylation in neurodevelopment by emphasizing changes of synaptic genes and proteins. Epigenetic causes of sex-dependent differences in the brain are analyzed in conjunction with the pathophysiology of autism spectrum disorders. Special attention is devoted to the epigenetic regulation of the melanoma-associated antigen-like gene 2 (MAGEL2) found in Prader-Willi syndrome, which is known to be accompanied by autistic symptoms.

scholarly journals Diagnostic and Treatment Approaches Involving Transthyretin in Amyloidogenic Diseases

2019 ◽  
Vol 20 (12) ◽  
pp. 2982 ◽  
Author(s):  
Gil Yong Park ◽  
Angelo Jamerlan ◽  
Kyu Hwan Shim ◽  
Seong Soo A. An
Keyword(s):  
Cerebrospinal Fluid ◽  
Genetic Mutations ◽  
Hormone Binding ◽  
Wild Type ◽  
Autonomic Motor ◽  
Hormone Binding Protein ◽  
The Brain ◽  
Tetrameric Form

Transthyretin (TTR) is a thyroid hormone-binding protein which transports thyroxine from the bloodstream to the brain. The structural stability of TTR in tetrameric form is crucial for maintaining its original functions in blood or cerebrospinal fluid (CSF). The altered structure of TTR due to genetic mutations or its deposits due to aggregation could cause several deadly diseases such as cardiomyopathy and neuropathy in autonomic, motor, and sensory systems. The early diagnoses for hereditary amyloid TTR with cardiomyopathy (ATTR-CM) and wild-type amyloid TTR (ATTRwt) amyloidosis, which result from amyloid TTR (ATTR) deposition, are difficult to distinguish due to the close similarities of symptoms. Thus, many researchers investigated the role of ATTR as a biomarker, especially its potential for differential diagnosis due to its varying pathogenic involvement in hereditary ATTR-CM and ATTRwt amyloidosis. As a result, the detection of ATTR became valuable in the diagnosis and determination of the best course of treatment for ATTR amyloidoses. Assessing the extent of ATTR deposition and genetic analysis could help in determining disease progression, and thus survival rate could be improved following the determination of the appropriate course of treatment for the patient. Here, the perspectives of ATTR in various diseases were presented.

scholarly journals Does microglial dysfunction play a role in autism and Rett syndrome?

2011 ◽  
Vol 7 (1) ◽  
pp. 85-97 ◽  
Author(s):  
Izumi Maezawa ◽  
Marco Calafiore ◽  
Heike Wulff ◽  
Lee-Way Jin
Keyword(s):  
Social Interactions ◽  
Rett Syndrome ◽  
Autism Spectrum ◽  
Developmental Trajectory ◽  
Repetitive Behaviors ◽  
Environmental Toxins ◽  
Communication Difficulties ◽  
Brain Circuitry ◽  
Spectrum Disorders

Autism spectrum disorders (ASDs) including classic autism is a group of complex developmental disabilities with core deficits of impaired social interactions, communication difficulties and repetitive behaviors. Although the neurobiology of ASDs has attracted much attention in the last two decades, the role of microglia has been ignored. Existing data are focused on their recognized role in neuroinflammation, which only covers a small part of the pathological repertoire of microglia. This review highlights recent findings on the broader roles of microglia, including their active surveillance of brain microenvironments and regulation of synaptic connectivity, maturation of brain circuitry and neurogenesis. Emerging evidence suggests that microglia respond to pre- and postnatal environmental stimuli through epigenetic interface to change gene expression, thus acting as effectors of experience-dependent synaptic plasticity. Impairments of these microglial functions could substantially contribute to several major etiological factors of autism, such as environmental toxins and cortical underconnectivity. Our recent study on Rett syndrome, a syndromic autistic disorder, provides an example that intrinsic microglial dysfunction due to genetic and epigenetic aberrations could detrimentally affect the developmental trajectory without evoking neuroinflammation. We propose that ASDs provide excellent opportunities to study the influence of microglia on neurodevelopment, and this knowledge could lead to novel therapies.

scholarly journals 7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome

2012 ◽  
Vol 112 (5) ◽  
pp. 704-710 ◽  
Author(s):  
Rebecca A. Johnson ◽  
Maxine Lam ◽  
Antonio M. Punzo ◽  
Hongda Li ◽  
Benjamin R. Lin ◽  
...  
Keyword(s):  
Disease Progression ◽  
Rett Syndrome ◽  
Developmental Disorder ◽  
Body Weight Loss ◽  
Autism Spectrum ◽  
Mutant Mice ◽  
Disease Symptoms ◽  
Neuronal Nuclei ◽  
Conditional Deletion ◽  
The Brain

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

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