In Silico Study of Rett Syndrome Treatment-Related Genes, MECP2, CDKL5, and FOXG1, by Evolutionary Classification and Disordered Region Assessment

Rett syndrome (RTT), a neurodevelopmental disorder, is mainly caused by mutations in methyl CpG-binding protein 2 (MECP2), which has multiple functions such as binding to methylated DNA or interacting with a transcriptional co-repressor complex. It has been established that alterations in cyclin-dependent kinase-like 5 (CDKL5) or forkhead box protein G1 (FOXG1) correspond to distinct neurodevelopmental disorders, given that a series of studies have indicated that RTT is also caused by alterations in either one of these genes. We investigated the evolution and molecular features of MeCP2, CDKL5, and FOXG1 and their binding partners using phylogenetic profiling to gain a better understanding of their similarities. We also predicted the structural order–disorder propensity and assessed the evolutionary rates per site of MeCP2, CDKL5, and FOXG1 to investigate the relationships between disordered structure and other related properties with RTT. Here, we provide insight to the structural characteristics, evolution and interaction landscapes of those three proteins. We also uncovered the disordered structure properties and evolution of those proteins which may provide valuable information for the development of therapeutic strategies of RTT.

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Phylogenetic Profiling and Disordered Region Assessment of MECP2, CDKL5, and FOXG1 to Reveal Strategies for Rett Syndrome Treatment

10.20944/preprints201911.0061.v1 ◽

2019 ◽

Author(s):

Muhamad Fahmi ◽

Gen Yasui ◽

Kaito Seki ◽

Syouichi Katayama ◽

Takako Kaneko-Kawano ◽

...

Keyword(s):

Rett Syndrome ◽

Catalytic Domain ◽

Neurodevelopmental Disorder ◽

Potential Candidate ◽

Disordered Structure ◽

Binding Partners ◽

C Terminus ◽

Phylogenetic Profiling ◽

And Function ◽

Insight Into

Rett syndrome (RTT), a neurodevelopmental disorder, is mainly caused by mutations in methyl CpG-binding protein 2 (MECP2), which alter the functions of domains to either bind to methylated DNA or interact with a transcriptional co-repressor complex. It has been established that alterations in cyclin-dependent kinase-like 5 (CDKL5) or forkhead box protein G1 (FOXG1) correspond to distinct neurodevelopmental disorders, given that a series of studies have indicated that RTT is also caused by alterations in either one of these genes. We tried to elucidate RTT through evolution and structure assessment of MeCP2, CDKL5, and FOXG1, by focusing on their binding partners and disordered structures. Here, we provide insight into the similarities of the FOXG1 and MECP2 binding partners evolution and function. On the other hand, we suggest that CDKL5 could be a potential candidate for a classical RTT treatment, particularly based on its disordered structure that spans after the catalytic domain to the C-terminus, which shows abundant linear motifs that can bind to molecules with divergent structures of similar affinity. Additionally, we provide insight into the relationship between disordered structure and disease.

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Cytokine Dysregulation inMECP2- andCDKL5-Related Rett Syndrome: Relationships with Aberrant Redox Homeostasis, Inflammation, andω-3 PUFAs

Oxidative Medicine and Cellular Longevity ◽

10.1155/2015/421624 ◽

2015 ◽

Vol 2015 ◽

pp. 1-18 ◽

Cited By ~ 33

Author(s):

Silvia Leoncini ◽

Claudio De Felice ◽

Cinzia Signorini ◽

Gloria Zollo ◽

Alessio Cortelazzo ◽

...

Keyword(s):

Rett Syndrome ◽

Neurodevelopmental Disorder ◽

Redox Homeostasis ◽

Clinical Severity ◽

Cyclin Dependent Kinase ◽

Omega 3 ◽

Inflammatory Status ◽

Cytokine Levels ◽

Before And After ◽

Cytokine Dysregulation

An involvement of the immune system has been suggested in Rett syndrome (RTT), a devastating neurodevelopmental disorder related to oxidative stress, and caused by a mutation in the methyl-CpG binding protein 2 gene (MECP2) or, more rarely, cyclin-dependent kinase-like 5 (CDKL5). To date, it is unclear whether both mutations may have an impact on the circulating cytokine patterns. In the present study, cytokines involved in the Th1-, Th2-, and T regulatory (T-reg) response, as well as chemokines, were investigated inMECP2- (MECP2-RTT) (n=16) andCDKL5-Rett syndrome (CDKL5-RTT) (n=8), before and afterω-3 polyunsaturated fatty acids (PUFAs) supplementation. A major cytokine dysregulation was evidenced in untreated RTT patients. InMECP2-RTT, a Th2-shifted balance was evidenced, whereas inCDKL5-RTT both Th1- and Th2-related cytokines (except for IL-4) were upregulated. InMECP2-RTT, decreased levels of IL-22 were observed, whereas increased IL-22 and T-reg cytokine levels were evidenced inCDKL5-RTT. Chemokines were unchanged. The cytokine dysregulation was proportional to clinical severity, inflammatory status, and redox imbalance. Omega-3 PUFAs partially counterbalanced cytokine changes, as well as aberrant redox homeostasis and the inflammatory status. RTT is associated with a subclinical immune dysregulation as the likely consequence of a defective inflammation regulatory signaling system.

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Cyclin-Dependent Kinase-Like 5 (CDKL5): Possible Cellular Signalling Targets and Involvement in CDKL5 Deficiency Disorder

Neural Plasticity ◽

10.1155/2020/6970190 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Syouichi Katayama ◽

Noriyuki Sueyoshi ◽

Tetsuya Inazu ◽

Isamu Kameshita

Keyword(s):

Catalytic Activity ◽

Rett Syndrome ◽

Neurodevelopmental Disorder ◽

Cyclin Dependent Kinase ◽

Loss Of Function ◽

Neuronal Function ◽

Transcriptional Mapping ◽

Target Molecules ◽

New Treatment ◽

The Relationship

Cyclin-dependent kinase-like 5 (CDKL5, also known as STK9) is a serine/threonine protein kinase originally identified in 1998 during a transcriptional mapping project of the human X chromosome. Thereafter, a mutation in CDKL5 was reported in individuals with the atypical Rett syndrome, a neurodevelopmental disorder, suggesting that CDKL5 plays an important regulatory role in neuronal function. The disease associated with CDKL5 mutation has recently been recognised as CDKL5 deficiency disorder (CDD) and has been distinguished from the Rett syndrome owing to its symptomatic manifestation. Because CDKL5 mutations identified in patients with CDD cause enzymatic loss of function, CDKL5 catalytic activity is likely strongly associated with the disease. Consequently, the exploration of CDKL5 substrate characteristics and regulatory mechanisms of its catalytic activity are important for identifying therapeutic target molecules and developing new treatment. In this review, we summarise recent findings on the phosphorylation of CDKL5 substrates and the mechanisms of CDKL5 phosphorylation and dephosphorylation. We also discuss the relationship between changes in the phosphorylation signalling pathways and the Cdkl5 knockout mouse phenotype and consider future prospects for the treatment of mental and neurological disease associated with CDKL5 mutations.

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Cyclin-Dependent Kinase-Like 5 (CDKL5) Mutation Screening in Rett Syndrome and Related Disorders

Twin Research and Human Genetics ◽

10.1375/twin.13.2.168 ◽

2010 ◽

Vol 13 (2) ◽

pp. 168-178 ◽

Cited By ~ 22

Author(s):

Rose White ◽

Gladys Ho ◽

Swetlana Schmidt ◽

Ingrid E. Scheffer ◽

Alexandra Fischer ◽

...

Keyword(s):

Rett Syndrome ◽

Early Onset ◽

De Novo ◽

Wide Spectrum ◽

Neurodevelopmental Disorder ◽

Mutation Screening ◽

Clinical Manifestations ◽

Epileptic Encephalopathy ◽

Cyclin Dependent Kinase ◽

Aicardi Syndrome

AbstractRett syndrome (RTT) is a severe neurodevelopmental disorder affecting females almost exclusively and is characterized by a wide spectrum of clinical manifestations. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been found in up to 95% of classical RTT cases and a lesser proportion of atypical cases. Recently, mutations in another X-linked gene, CDKL5 (cyclin-dependent kinase-like 5) have been found to cause atypical RTT, in particular the early onset seizure (Hanefeld variant) and one female with autism. In this study we screened several cohorts of children for CDKL5 mutations, totaling 316 patients, including individuals with a clinical diagnosis of RTT but who were negative for MECP2 mutations (n = 102), males with X-linked mental retardation (n = 9), patients with West syndrome (n = 52), patients with autism (n = 59), patients with epileptic encephalopathy (n = 33), patients with Aicardi syndrome (n = 7) and other patients with intellectual disability with or without seizures (n = 54). In all, seven polymorphic variations and four de novo mutations (c.586C>T [p.S196L]; c.58G>C [p.G20R]; c.2504delC [p.P835fs]; deletion of exons 1 - 3) were identified, and in all instances of the latter the clinical phenotype was that of an epileptic encephalopathy. These results suggest that pathogenic CDKL5 mutations are unlikely to be identified in the absence of severe early-onset seizures and highlight the importance of screening for large intragenic and whole gene deletions.

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Immune Dysfunction in Rett Syndrome Patients Revealed by High Levels of Serum Anti-N(Glc) IgM Antibody Fraction

Journal of Immunology Research ◽

10.1155/2014/260973 ◽

2014 ◽

Vol 2014 ◽

pp. 1-6 ◽

Cited By ~ 10

Author(s):

Anna Maria Papini ◽

Francesca Nuti ◽

Feliciana Real-Fernandez ◽

Giada Rossi ◽

Caterina Tiberi ◽

...

Keyword(s):

Immune System ◽

Rett Syndrome ◽

Pervasive Developmental Disorders ◽

Developmental Disorders ◽

Neurodevelopmental Disorder ◽

Loss Of Function ◽

Gene Encoding ◽

Antibody Recognition ◽

Forkhead Box ◽

Significant Difference

Rett syndrome (RTT), a neurodevelopmental disorder affecting exclusively (99%) female infants, is associated with loss-of-function mutations in the gene encoding methyl-CpG binding protein 2 (MECP2) and, more rarely, cyclin-dependent kinase-like 5 (CDKL5) and forkhead box protein G1 (FOXG1). In this study, we aimed to evaluate the function of the immune system by measuring serum immunoglobulins (IgG and IgM) in RTT patients (n=53) and, by comparison, in age-matched children affected by non-RTT pervasive developmental disorders (non-RTT PDD) (n=82) and healthy age-matched controls (n=29). To determine immunoglobulins we used both a conventional agglutination assay and a novel ELISA based on antibody recognition by a surrogate antigen probe, CSF114(Glc), a syntheticN-glucosylated peptide. Both assays provided evidence for an increase in IgM titer, but not in IgG, in RTT patients relative to both healthy controls and non-RTT PDD patients. The significant difference in IgM titers between RTT patients and healthy subjects in the CSF114(Glc) assay (P=0.001) suggests that this procedure specifically detects a fraction of IgM antibodies likely to be relevant for the RTT disease. These findings offer a new insight into the mechanism underlying the Rett disease as they unveil the possible involvement of the immune system in this pathology.

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

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-021-09358-1 ◽

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.

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Small-molecule degraders of cyclin-dependent kinase protein: a review

Future Medicinal Chemistry ◽

10.4155/fmc-2021-0154 ◽

2021 ◽

Author(s):

Bin Yu ◽

Zekun Du ◽

Yuming Zhang ◽

Zhiyu Li ◽

Jinlei Bian

Keyword(s):

Cell Cycle ◽

Drug Resistance ◽

Protein Degradation ◽

Small Molecule ◽

Small Molecule Inhibitors ◽

Structural Characteristics ◽

Protein A ◽

Cyclin Dependent Kinase ◽

Chemical Tools ◽

Potential Therapeutics

Proteolysis-targeting chimeras are a new modality of chemical tools and potential therapeutics involving the induction of protein degradation. Cyclin-dependent kinase (CDK) protein, which is involved in cycles and transcription cycles, participates in regulation of the cell cycle, transcription and splicing. Proteolysis-targeting chimeras targeting CDKs show several advantages over traditional CDK small-molecule inhibitors in potency, selectivity and drug resistance. In addition, the discovery of molecule glues promotes the development of CDK degraders. Herein, the authors describe the existing CDK degraders and focus on the discussion of the structural characteristics and design of these degraders.

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Consensus guidelines on managing Rett syndrome across the lifespan

BMJ Paediatrics Open ◽

10.1136/bmjpo-2020-000717 ◽

2020 ◽

Vol 4 (1) ◽

pp. e000717

Author(s):

Cary Fu ◽

Dallas Armstrong ◽

Eric Marsh ◽

David Lieberman ◽

Kathleen Motil ◽

...

Keyword(s):

Primary Care ◽

Rett Syndrome ◽

Health Professionals ◽

Best Practice ◽

Neurodevelopmental Disorder ◽

Primary Care Providers ◽

Care Providers ◽

Medical Comorbidities ◽

Modified Delphi ◽

Delphi Approach

BackgroundRett syndrome (RTT) is a severe neurodevelopmental disorder with complex medical comorbidities extending beyond the nervous system requiring the attention of health professionals. There is no peer-reviewed, consensus-based therapeutic guidance to care in RTT. The objective was to provide consensus on guidance of best practice for addressing these concerns.MethodsInformed by the literature and using a modified Delphi approach, a consensus process was used to develop guidance for care in RTT by health professionals.ResultsTypical RTT presents early in childhood in a clinically recognisable fashion. Multisystem comorbidities evolve throughout the lifespan requiring coordination of care between primary care and often multiple subspecialty providers. To assist health professionals and families in seeking best practice, a checklist and detailed references for guidance were developed by consensus.ConclusionsThe overall multisystem issues of RTT require primary care providers and other health professionals to manage complex medical comorbidities within the context of the whole individual and family. Given the median life expectancy well into the sixth decade, guidance is provided to health professionals to achieve current best possible outcomes for these special-needs individuals.

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Rett Syndrome in Males: The Different Clinical Course in Two Brothers with the Same Microduplication MECP2 Xq28

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16173075 ◽

2019 ◽

Vol 16 (17) ◽

pp. 3075

Author(s):

Maria Bernarda Pitzianti ◽

Angelo Santamaria Palombo ◽

Susanna Esposito ◽

Augusto Pasini

Keyword(s):

Rett Syndrome ◽

Genetic Basis ◽

Normal Development ◽

Clinical Course ◽

Neurodevelopmental Disorder ◽

Dominant Inheritance ◽

Clinical Form ◽

Inactivation Pattern ◽

History Of

Rett syndrome (RTT) is a neurodevelopmental disorder with a genetic basis that is associated with the mutation of the X-linked methyl-CpG binding protein 2 (MECP2) gene in approximately 90% of patients. RTT is characterized by a brief period of normal development followed by loss of acquired skills and evolution towards impairment of brain and motor functions and multi-organ dysfunction. Originally, RTT was considered lethal in males as it has an X-linked dominant inheritance. However, although this syndrome has a higher incidence in females, rare cases are also documented in males. Here, we describe the case of an 11-year-old male patient with a microduplication MECP2 Xq28. Our patient is currently living, while his older brother with the same mutation died at the age of 9 years. We showed that the role of MECP2 as an epigenetic modulator and the X-chromosome inactivation pattern can explain the lethal clinical form of the older brother with the same microduplication MECP2 Xq28 presented by our patient who is still alive. Given the limited case history of RTT in males, further studies are needed to better characterize this syndrome in males and consequently improve the currently available therapeutic strategies.

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Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome

eLife ◽

10.7554/elife.14198 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 53

Author(s):

Kerstin Ure ◽

Hui Lu ◽

Wei Wang ◽

Aya Ito-Ishida ◽

Zhenyu Wu ◽

...

Keyword(s):

Social Skills ◽

Mouse Model ◽

Rett Syndrome ◽

Therapeutic Option ◽

Neurodevelopmental Disorder ◽

Gabaergic Neurons ◽

Inhibitory Neurons ◽

Extended Lifespan ◽

Inhibitory Signaling

The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2+/- mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome.

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