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Molecular Research on Rett Syndrome and Related Disorders: From the Past towards the Future 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 15647

Special Issue Editors

Prof. Dr. Nicoletta Landsberger

E-Mail Website
Guest Editor
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
Interests: Rett syndrome; MeCP2; CDKL5; epigenetics; neurodevelopment
Special Issues, Collections and Topics in MDPI journals
Dr. Angelisa Frasca

E-Mail Website
Guest Editor
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
Interests: Rett syndrome and related disorders; neuroscience; neuropharmacology; molecular biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is our pleasure to announce that we have accepted, for the second time, the invitation to edit a IJMS issue dedicated to Rett syndrome and related disorders. The first issue dates back to 2019 and gathered 13 different articles that were, on average, visited at least 2000 times. We thought that this result was a good indication of how important a second issue would be, in which original works and reviews can be gathered together.

After the milestone discovery that, at least in mice, Rett syndrome and possibly related disorders are not irreversible conditions, dramatic progress has been achieved, leading researchers to reveal novel biological roles of the involved genes and to identify the affected molecular pathways and cellular processes. Accordingly, it seems that we are really close to the first FDA-approved treatment for Rett syndrome, with more therapeutic options to come in future years. The ambition is that altogether, our works dedicated to Rett syndrome will continue to increase the knowledge on the pathogenesis of this devastating disorder, providing geneticists and clinicians with novel molecular diagnostic tools and therapeutic targets, and researchers with novel strategies.

Considering all of the above, in this issue, we will collect manuscripts focusing on Rett syndrome and related disorders, spanning from genetics to basic scientific findings and preclinical studies. The final goal is to present readers with an updated view of the state of art and frontiers of research on RTT.

Prof. Dr. Nicoletta Landsberger
Dr. Angelisa Frasca
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • MECP2 and its molecular roles
  • CDKL5 and its molecular roles
  • FOXG1 and its molecular roles
  • Novel genes associated with Rett syndrome and related disorders
  • Molecular dysfunctions in Rett syndrome and related disorders
  • Therapeutic approaches for Rett syndrome and related disorders

Published Papers (5 papers)

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Research

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26 pages, 7138 KiB  
Article
The Chromatin Structure at the MECP2 Gene and In Silico Prediction of Potential Coding and Non-Coding MECP2 Splice Variants
by Danilo Shevkoplyas, Yen My Vuu, James R. Davie and Mojgan Rastegar
Int. J. Mol. Sci. 2022, 23(24), 15643; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415643 - 09 Dec 2022
Cited by 5 | Viewed by 1817
Abstract
Methyl CpG binding protein 2 (MeCP2) is an epigenetic reader that binds to methylated CpG dinucleotides and regulates gene transcription. Mecp2/MECP2 gene has 4 exons, encoding for protein isoforms MeCP2E1 and MeCP2E2. MeCP2 plays key roles in neurodevelopment, therefore, its gain- [...] Read more.
Methyl CpG binding protein 2 (MeCP2) is an epigenetic reader that binds to methylated CpG dinucleotides and regulates gene transcription. Mecp2/MECP2 gene has 4 exons, encoding for protein isoforms MeCP2E1 and MeCP2E2. MeCP2 plays key roles in neurodevelopment, therefore, its gain- and loss-of-function mutations lead to neurodevelopmental disorders including Rett Syndrome. Here, we describe the structure, functional domains, and evidence support for potential additional alternatively spliced MECP2 transcripts and protein isoforms. We conclude that NCBI MeCP2 isoforms 3 and 4 contain certain MeCP2 functional domains. Our in silico analysis led to identification of histone modification and accessibility profiles at the MECP2 gene and its cis-regulatory elements. We conclude that the human MECP2 gene associated histone post-translational modifications exhibit high similarity between males and females. Between brain regions, histone modifications were found to be less conserved and enriched within larger genomic segments named as “S1–S11”. We also identified highly conserved DNA accessibility regions in different tissues and brain regions, named as “A1–A9” and “B1–B9”. DNA methylation profile was similar between mid-frontal gyrus of donors 35 days–25 years of age. Based on ATAC-seq data, the identified hypomethylated regions “H1–H8” intersected with most regions of the accessible chromatin (A regions). Full article
(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders: From the Past towards the Future 2.0)
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12 pages, 5465 KiB  
Article
Comprehensive In Silico Functional Prediction Analysis of CDKL5 by Single Amino Acid Substitution in the Catalytic Domain
by Yuri Yoshimura, Atsushi Morii, Yuuki Fujino, Marina Nagase, Arisa Kitano, Shiho Ueno, Kyoka Takeuchi, Riko Yamashita and Tetsuya Inazu
Int. J. Mol. Sci. 2022, 23(20), 12281; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012281 - 14 Oct 2022
Viewed by 1068
Abstract
Cyclin-dependent kinase-like 5 (CDKL5) is a serine/threonine protein kinase whose pathological mutations cause CDKL5 deficiency disorder. Most missense mutations are concentrated in the catalytic domain. Therefore, anticipating whether mutations in this region affect CDKL5 function is informative for clinical diagnosis. This study comprehensively [...] Read more.
Cyclin-dependent kinase-like 5 (CDKL5) is a serine/threonine protein kinase whose pathological mutations cause CDKL5 deficiency disorder. Most missense mutations are concentrated in the catalytic domain. Therefore, anticipating whether mutations in this region affect CDKL5 function is informative for clinical diagnosis. This study comprehensively predicted the pathogenicity of all 5700 missense substitutions in the catalytic domain of CDKL5 using in silico analysis and evaluating their accuracy. Each missense substitution was evaluated as “pathogenic” or “benign”. In silico tools PolyPhen-2 HumDiv mode/HumVar mode, PROVEAN, and SIFT were selected individually or in combination with one another to determine their performance using 36 previously reported mutations as a reference. Substitutions predicted as pathogenic were over 88.0% accurate using each of the three tools. The best performance score (accuracy, 97.2%; sensitivity, 100%; specificity, 66.7%; and Matthew’s correlation coefficient (MCC), 0.804) was achieved by combining PolyPhen-2 HumDiv, PolyPhen-2 HumVar, and PROVEAN. This provided comprehensive information that could accurately predict the pathogenicity of the disease, which might be used as an aid for clinical diagnosis. Full article
(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders: From the Past towards the Future 2.0)
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21 pages, 2617 KiB  
Article
Anti-Semaphorin 4D Rescues Motor, Cognitive, and Respiratory Phenotypes in a Rett Syndrome Mouse Model
by Yilin Mao, Elizabeth E. Evans, Vikas Mishra, Leslie Balch, Allison Eberhardt, Maurice Zauderer and Wendy A. Gold
Int. J. Mol. Sci. 2021, 22(17), 9465; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179465 - 31 Aug 2021
Cited by 5 | Viewed by 3724
Abstract
Rett syndrome is a neurodevelopmental disorder caused by mutations of the methyl-CpG binding protein 2 gene. Abnormal physiological functions of glial cells contribute to pathogenesis of Rett syndrome. Semaphorin 4D (SEMA4D) regulates processes central to neuroinflammation and neurodegeneration including cytoskeletal structures required for [...] Read more.
Rett syndrome is a neurodevelopmental disorder caused by mutations of the methyl-CpG binding protein 2 gene. Abnormal physiological functions of glial cells contribute to pathogenesis of Rett syndrome. Semaphorin 4D (SEMA4D) regulates processes central to neuroinflammation and neurodegeneration including cytoskeletal structures required for process extension, communication, and migration of glial cells. Blocking SEMA4D-induced gliosis may preserve normal glial and neuronal function and rescue neurological dysfunction in Rett syndrome. We evaluated the pre-clinical therapeutic efficacy of an anti-SEMA4D monoclonal antibody in the Rett syndrome Mecp2T158A transgenic mouse model and investigated the contribution of glial cells as a proposed mechanism of action in treated mice and in primary glial cultures isolated from Mecp2T158A/y mutant mice. SEMA4D is upregulated in neurons while glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1-positive cells are upregulated in Mecp2T158A/y mice. Anti-SEMA4D treatment ameliorates Rett syndrome-specific symptoms and improves behavioural functions in both pre-symptomatic and symptomatic cohorts of hemizygous Mecp2T158A/y male mice. Anti-SEMA4D also reduces astrocyte and microglia activation in vivo. In vitro experiments demonstrate an abnormal cytoskeletal structure in mutant astrocytes in the presence of SEMA4D, while anti-SEMA4D antibody treatment blocks SEMA4D–Plexin B1 signaling and mitigates these abnormalities. These results suggest that anti-SEMA4D immunotherapy may be an effective treatment option to alleviate symptoms and improve cognitive and motor function in Rett syndrome. Full article
(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders: From the Past towards the Future 2.0)
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Review

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19 pages, 1580 KiB  
Review
Technological Improvements in the Genetic Diagnosis of Rett Syndrome Spectrum Disorders
by Clara Xiol, Maria Heredia, Ainhoa Pascual-Alonso, Alfonso Oyarzabal and Judith Armstrong
Int. J. Mol. Sci. 2021, 22(19), 10375; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910375 - 26 Sep 2021
Cited by 5 | Viewed by 2980
Abstract
Rett syndrome (RTT) is a severe neurodevelopmental disorder that constitutes the second most common cause of intellectual disability in females worldwide. In the past few years, the advancements in genetic diagnosis brought by next generation sequencing (NGS), have made it possible to identify [...] Read more.
Rett syndrome (RTT) is a severe neurodevelopmental disorder that constitutes the second most common cause of intellectual disability in females worldwide. In the past few years, the advancements in genetic diagnosis brought by next generation sequencing (NGS), have made it possible to identify more than 90 causative genes for RTT and significantly overlapping phenotypes (RTT spectrum disorders). Therefore, the clinical entity known as RTT is evolving towards a spectrum of overlapping phenotypes with great genetic heterogeneity. Hence, simultaneous multiple gene testing and thorough phenotypic characterization are mandatory to achieve a fast and accurate genetic diagnosis. In this review, we revise the evolution of the diagnostic process of RTT spectrum disorders in the past decades, and we discuss the effectiveness of state-of-the-art genetic testing options, such as clinical exome sequencing and whole exome sequencing. Moreover, we introduce recent technological advancements that will very soon contribute to the increase in diagnostic yield in patients with RTT spectrum disorders. Techniques such as whole genome sequencing, integration of data from several “omics”, and mosaicism assessment will provide the tools for the detection and interpretation of genomic variants that will not only increase the diagnostic yield but also widen knowledge about the pathophysiology of these disorders. Full article
(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders: From the Past towards the Future 2.0)
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16 pages, 508 KiB  
Review
MECP2-Related Disorders in Males
by Ainhoa Pascual-Alonso, Antonio F. Martínez-Monseny, Clara Xiol and Judith Armstrong
Int. J. Mol. Sci. 2021, 22(17), 9610; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179610 - 04 Sep 2021
Cited by 16 | Viewed by 5268
Abstract
Methyl CpG binding protein 2 (MECP2) is located at Xq28 and is a multifunctional gene with ubiquitous expression. Loss-of-function mutations in MECP2 are associated with Rett syndrome (RTT), which is a well-characterized disorder that affects mainly females. In boys, however, mutations [...] Read more.
Methyl CpG binding protein 2 (MECP2) is located at Xq28 and is a multifunctional gene with ubiquitous expression. Loss-of-function mutations in MECP2 are associated with Rett syndrome (RTT), which is a well-characterized disorder that affects mainly females. In boys, however, mutations in MECP2 can generate a wide spectrum of clinical presentations that range from mild intellectual impairment to severe neonatal encephalopathy and premature death. Thus, males can be more difficult to classify and diagnose than classical RTT females. In addition, there are some variants of unknown significance in MECP2, which further complicate the diagnosis of these children. Conversely, the entire duplication of the MECP2 gene is related to MECP2 duplication syndrome (MDS). Unlike in RTT, in MDS, males are predominantly affected. Usually, the duplication is inherited from an apparently asymptomatic carrier mother. Both syndromes share some characteristics, but also differ in some aspects regarding the clinical picture and evolution. In the following review, we present a thorough description of the different types of MECP2 variants and alterations that can be found in males, and explore several genotype–phenotype correlations, although there is still a lot to understand. Full article
(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders: From the Past towards the Future 2.0)
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