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

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.

scholarly journals Sphingolipid Metabolism Perturbations in Rett Syndrome

Metabolites ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 221 ◽  
Author(s):  
Cappuccio ◽  
Donti ◽  
Pinelli ◽  
Bernardo ◽  
Bravaccio ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Metabolic Profiling ◽  
Neurodevelopmental Disorder ◽  
Sphingolipid Metabolism ◽  
Tandem Mass ◽  
Mecp2 Gene ◽  
Loss Of Function ◽  
Disease Pathogenesis ◽  
Blood Samples ◽  
Disease Biomarkers

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

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

2015 ◽  
Vol 2015 ◽  
pp. 1-18 ◽  
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.

scholarly journals The relationship of Rett syndrome and MECP2 disorders to autism

2012 ◽  
Vol 14 (3) ◽  
pp. 253-262 ◽  
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Protein Product ◽  
The Many ◽  
Clinical Conditions ◽  
Relationship Of ◽  
The Relationship ◽  
Clinical Problems ◽  
Insight Into

Rett syndrome (RTT, MIM#312750) is a neurodevelopmental disorder that is classified as an autism spectrum disorder. Clinically, RTT is characterized by psychomotor regression with loss of volitional hand use and spoken language, the development of repetitive hand stereotypies, and gait impairment. The majority of people with RTT have mutations in Methyl-CpG-binding Protein 2 (MECP2), a transcriptional regulator. Interestingly, alterations in the function of the protein product produced by MECP2, MeCP2, have been identified in a number of other clinical conditions. The many clinical features found in RTT and the various clinical problems that result from alteration in MeCP2 function have led to the belief that understanding RTT will provide insight into a number of other neurological disorders. Excitingly, RTT is reversible in a mouse model, providing inspiration and hope that such a goal may be achieved for RTT and potentially for many neurodevelopmental disorders.

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

2010 ◽  
Vol 13 (2) ◽  
pp. 168-178 ◽  
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.

Clinical, Molecular, and Computational Analysis in Patients With a Novel Double Mutation and a New Synonymous Variant in MeCP2: Report of the First Missense Mutation Within the AT-hook1 Cluster in Rett Syndrome

2017 ◽  
Vol 32 (8) ◽  
pp. 694-703 ◽  
Author(s):  
Marwa Kharrat ◽  
Yosra Kamoun ◽  
Fatma Kamoun ◽  
Emna Ellouze ◽  
Marwa Maalej ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Rett Syndrome ◽  
Phenotypic Variability ◽  
Neurodevelopmental Disorder ◽  
Clinical Severity ◽  
Bioinformatics Analyses ◽  
Double Mutation ◽  
Synonymous Variant ◽  
In Cis ◽  
The Relationship

Rett syndrome is an X-linked neurodevelopmental disorder, primarily caused by MECP2 mutations. In this study, clinical, molecular and bioinformatics analyses were performed in Rett patients to understand the relationship between MECP2 mutation type and the clinical severity. Two double MeCP2 mutations were detected: a novel one (p.G185 V in cis with p.R255X) in P1 and a known one (p.P179 S in cis with p.R255X) in P2. Besides, a novel synonymous mutation (c.807C>T; p.G269G), which could affect mRNA splicing, was identified in P3. The results from clinical severity analysis have shown that P1 was more severely affected than P2 with CSS being 35 and 14, respectively. Therefore, the phenotypic variability in P1 and P2 could be explained by the potential pathogenic effect of the RTT-causing missense mutation p.G185 V in the AT-hook1. In conclusion, clinical, molecular, and in silico investigations in the studied patients have been proven to be substantial for the genotype-phenotype correlation.

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

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
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.

scholarly journals Subclinical Inflammatory Status in Rett Syndrome

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Alessio Cortelazzo ◽  
Claudio De Felice ◽  
Roberto Guerranti ◽  
Cinzia Signorini ◽  
Silvia Leoncini ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Rett Syndrome ◽  
De Novo ◽  
Clinical Chemistry ◽  
Neurodevelopmental Disorder ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Protein Levels ◽  
Large Deletions ◽  
Inflammatory Status

Inflammation has been advocated as a possible common central mechanism for developmental cognitive impairment. Rett syndrome (RTT) is a devastating neurodevelopmental disorder, mainly caused byde novoloss-of-function mutations in the gene encoding MeCP2. Here, we investigated plasma acute phase response (APR) in stage II (i.e., “pseudo-autistic”) RTT patients by routine haematology/clinical chemistry and proteomic 2-DE/MALDI-TOF analyses as a function of four majorMECP2gene mutation types (R306C, T158M, R168X, and large deletions). Elevated erythrocyte sedimentation rate values (median 33.0 mm/h versus 8.0 mm/h,P<0.0001) were detectable in RTT, whereas C-reactive protein levels were unchanged (P=0.63). The 2-DE analysis identified significant changes for a total of 17 proteins, the majority of which were categorized as APR proteins, either positive (n=6spots) or negative (n=9spots), and to a lesser extent as proteins involved in the immune system (n=2spots), with some proteins having overlapping functions on metabolism (n=7spots). The number of protein changes was proportional to the severity of the mutation. Our findings reveal for the first time the presence of a subclinical chronic inflammatory status related to the “pseudo-autistic” phase of RTT, which is related to the severity carried by theMECP2gene mutation.

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

2019 ◽  
Vol 20 (22) ◽  
pp. 5593 ◽  
Author(s):  
Muhamad Fahmi ◽  
Gen Yasui ◽  
Kaito Seki ◽  
Syouichi Katayama ◽  
Takako Kaneko-Kawano ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Structural Characteristics ◽  
Neurodevelopmental Disorder ◽  
Cyclin Dependent Kinase ◽  
Disordered Structure ◽  
Molecular Features ◽  
Forkhead Box ◽  
In Silico Study ◽  
Repressor Complex ◽  
Phylogenetic Profiling

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.

scholarly journals JNK signaling provides a novel therapeutic target for Rett syndrome

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Clara Alice Musi ◽  
Anna Maria Castaldo ◽  
Anna Elisa Valsecchi ◽  
Sara Cimini ◽  
Noemi Morello ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Clinical Symptoms ◽  
Neurodevelopmental Disorder ◽  
Loss Of Function ◽  
Jnk Signaling ◽  
Functional Changes ◽  
Jnk Activation ◽  
Stress Pathway

Abstract Background Rett syndrome (RTT) is a monogenic X-linked neurodevelopmental disorder characterized by loss-of-function mutations in the MECP2 gene, which lead to structural and functional changes in synapse communication, and impairments of neural activity at the basis of cognitive deficits that progress from an early age. While the restoration of MECP2 in animal models has been shown to rescue some RTT symptoms, gene therapy intervention presents potential side effects, and with gene- and RNA-editing approaches still far from clinical application, strategies focusing on signaling pathways downstream of MeCP2 may provide alternatives for the development of more effective therapies in vivo. Here, we investigate the role of the c-Jun N-terminal kinase (JNK) stress pathway in the pathogenesis of RTT using different animal and cell models and evaluate JNK inhibition as a potential therapeutic approach. Results We discovered that the c-Jun N-terminal kinase (JNK) stress pathway is activated in Mecp2-knockout, Mecp2-heterozygous mice, and in human MECP2-mutated iPSC neurons. The specific JNK inhibitor, D-JNKI1, promotes recovery of body weight and locomotor impairments in two mouse models of RTT and rescues their dendritic spine alterations. Mecp2-knockout presents intermittent crises of apnea/hypopnea, one of the most invalidating RTT pathological symptoms, and D-JNKI1 powerfully reduces this breathing dysfunction. Importantly, we discovered that also neurons derived from hiPSC-MECP2 mut show JNK activation, high-phosphorylated c-Jun levels, and cell death, which is not observed in the isogenic control wt allele hiPSCs. Treatment with D-JNKI1 inhibits neuronal death induced by MECP2 mutation in hiPSCs mut neurons. Conclusions As a summary, we found altered JNK signaling in models of RTT and suggest that D-JNKI1 treatment prevents clinical symptoms, with coherent results at the cellular, molecular, and functional levels. This is the first proof of concept that JNK plays a key role in RTT and its specific inhibition offers a new and potential therapeutic tool to tackle RTT.

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

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1533 ◽  
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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