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

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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 (31 July 2019) | Viewed by 86820

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Prof. Dr. Nicoletta Landsberger

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Guest Editor

1. Department of Medical Biotechnology and Translational Medicine, University of Milan, Italy
2. IRCCS San Raffaele Hospital/Division of Neuroscience, Milan, Italy
Interests: Rett syndrome; MeCP2; CDKL5; epigenetics; neurodevelopment
Special Issues, Collections and Topics in MDPI journals

Dr. Angelisa Frasca

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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 Colleague,

Dramatic progress has been made since the MECP2 gene was discovered as the main cause of Rett syndrome, providing geneticists with molecular diagnostic tools and researchers with a plethora of animal models and molecular pathways that might be relevant for treatments. Importantly, several laboratories have been able to demonstrate that Rett syndrome, and possibly related disorders, are not irreversible conditions, at least in mice. This has boosted research on the pathophysiology of these diseases, the biological roles of the involved genes, and the identification of the affected molecular pathways.

Despite this enormous acceleration of research in Rett syndrome and related disorders, no cure is still available. The identification of valid therapeutic approaches will certainly benefit from the development of new basic and pre-clinical studies based on a critical analysis of past molecular research.

Considering all of the above, we would like to invite original articles or reviews that focus on genes involved in Rett syndrome and related disorders, including MECP2, CDKL5, and FOXG1, and highlight deregulated molecular mechanisms, their potential involvement in the pathophysiology, and their therapeutic value.

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

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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 (13 papers)

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Research

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28 pages, 35153 KiB

Open AccessArticle

ATRX Contributes to MeCP2-Mediated Pericentric Heterochromatin Organization during Neural Differentiation

by Domenico Marano, Salvatore Fioriniello, Francesca Fiorillo, Richard J. Gibbons, Maurizio D’Esposito and Floriana Della Ragione

Int. J. Mol. Sci. 2019, 20(21), 5371; https://doi.org/10.3390/ijms20215371 - 29 Oct 2019

Cited by 19 | Viewed by 6603

Abstract

Methyl-CpG binding protein 2 (MeCP2) is a multi-function factor involved in locus-specific transcriptional modulation and the regulation of genome architecture, e.g., pericentric heterochromatin (PCH) organization. MECP2 mutations are responsible for Rett syndrome (RTT), a devastating postnatal neurodevelopmental disorder, the pathogenetic mechanisms of which are still unknown. MeCP2, together with Alpha-thalassemia/mental retardation syndrome X-linked protein (ATRX), accumulates at chromocenters, which are repressive PCH domains. As with MECP2, mutations in ATRX cause ATR-X syndrome which is associated with severe intellectual disability. We exploited two murine embryonic stem cell lines, in which the expression of MeCP2 or ATRX is abolished. Through immunostaining, chromatin immunoprecipitation and western blot, we show that MeCP2 and ATRX are reciprocally dependent both for their expression and targeting to chromocenters. Moreover, ATRX plays a role in the accumulation of members of the heterochromatin protein 1 (HP1) family at PCH and, as MeCP2, modulates their expression. Furthermore, ATRX and HP1 targeting to chromocenters depends on an RNA component. 3D-DNA fluorescence in situ hybridization (FISH) highlighted, for the first time, a contribution of ATRX in MeCP2-mediated chromocenter clustering during neural differentiation. Overall, we provide a detailed dissection of the functional interplay between MeCP2 and ATRX in higher-order PCH organization in neurons. Our findings suggest molecular defects common to RTT and ATR-X syndrome, including an alteration in PCH. Full article

(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders: From the Past Towards the Future)

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16 pages, 1732 KiB

Open AccessArticle

Splicing Mutations Impairing CDKL5 Expression and Activity Can be Efficiently Rescued by U1snRNA-Based Therapy

by Dario Balestra, Domenico Giorgio, Matteo Bizzotto, Maria Fazzari, Bruria Ben Zeev, Mirko Pinotti, Nicoletta Landsberger and Angelisa Frasca

Int. J. Mol. Sci. 2019, 20(17), 4130; https://doi.org/10.3390/ijms20174130 - 24 Aug 2019

Cited by 19 | Viewed by 4183

Abstract

Mutations in the CDKL5 gene lead to an incurable rare neurological condition characterized by the onset of seizures in the first weeks of life and severe intellectual disability. Replacement gene or protein therapies could represent intriguing options, however, their application may be inhibited by the recent demonstration that CDKL5 is dosage sensitive. Conversely, correction approaches acting on pre-mRNA splicing would preserve CDKL5 physiological regulation. Since ~15% of CDKL5 pathogenic mutations are candidates to affect splicing, we evaluated the capability of variants of the spliceosomal U1 small nuclear RNA (U1snRNA) to correct mutations affecting +1 and +5 nucleotides at the 5′ donor splice site and predicted to cause exon skipping. Our results show that CDKL5 minigene variants expressed in mammalian cells are a valid approach to assess CDKL5 splicing pattern. The expression of engineered U1snRNA effectively rescued mutations at +5 but not at the +1 nucleotides. Importantly, we proved that U1snRNA-mediated splicing correction fully restores CDKL5 protein synthesis, subcellular distribution and kinase activity. Eventually, by correcting aberrant splicing of an exogenously expressed splicing-competent CDKL5 transgene, we provided insights on the morphological rescue of CDKL5 null neurons, reporting the first proof-of-concept of the therapeutic value of U1snRNA-mediated CDKL5 splicing correction. Full article

(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders: From the Past Towards the Future)

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10 pages, 1139 KiB

Open AccessArticle

Cortical Seizures in FoxG1^+/− Mice are Accompanied by Akt/S6 Overactivation, Excitation/Inhibition Imbalance and Impaired Synaptic Transmission

by Giovanna Testa, Francesco Olimpico, Laura Pancrazi, Ugo Borello, Antonino Cattaneo, Matteo Caleo, Mario Costa and Marco Mainardi

Int. J. Mol. Sci. 2019, 20(17), 4127; https://doi.org/10.3390/ijms20174127 - 24 Aug 2019

Cited by 15 | Viewed by 3149

Abstract

The correct morphofunctional shaping of the cerebral cortex requires a continuous interaction between intrinsic (genes/molecules expressed within the tissue) and extrinsic (e.g., neural activity) factors at all developmental stages. Forkhead Box G1 (FOXG1) is an evolutionarily conserved transcription factor, essential for the cerebral cortex patterning and layering. FOXG1-related disorders, including the congenital form of Rett syndrome, can be caused by deletions, intragenic mutations or duplications. These genetic alterations are associated with a complex phenotypic spectrum, spanning from intellectual disability, microcephaly, to autistic features, and epilepsy. We investigated the functional correlates of dysregulated gene expression by performing electrophysiological assays on FoxG1^+/− mice. Local Field Potential (LFP) recordings on freely moving animals detected cortical hyperexcitability. On the other hand, patch-clamp recordings showed a downregulation of spontaneous glutamatergic transmission. These findings were accompanied by overactivation of Akt/S6 signaling. Furthermore, the expression of vesicular glutamate transporter 2 (vGluT2) was increased, whereas the level of the potassium/chloride cotransporter KCC2 was reduced, thus indicating a higher excitation/inhibition ratio. Our findings provide evidence that altered expression of a key gene for cortical development can result in specific alterations in neural circuit function at the macro- and micro-scale, along with dysregulated intracellular signaling and expression of proteins controlling circuit excitability. Full article

(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders: From the Past Towards the Future)

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18 pages, 1250 KiB

Open AccessArticle

Pathogenic Variants in STXBP1 and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes

by Francesca Cogliati, Valentina Giorgini, Maura Masciadri, Maria Teresa Bonati, Margherita Marchi, Irene Cracco, Davide Gentilini, Angela Peron, Miriam Nella Savini, Luigina Spaccini, Barbara Scelsa, Silvia Maitz, Edvige Veneselli, Giulia Prato, Maria Pintaudi, Isabella Moroni, Aglaia Vignoli, Lidia Larizza and Silvia Russo

Int. J. Mol. Sci. 2019, 20(15), 3621; https://doi.org/10.3390/ijms20153621 - 24 Jul 2019

Cited by 26 | Viewed by 5025

Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder, affecting 1 in 10,000 girls. Intellectual disability, loss of speech and hand skills with stereotypies, seizures and ataxia are recurrent features. Stringent diagnostic criteria distinguish classical Rett, caused by a MECP2 pathogenic variant in 95% of cases, from atypical girls, 40–73% carrying MECP2 variants, and rarely CDKL5 and FOXG1 alterations. A large fraction of atypical and RTT-like patients remain without genetic cause. Next Generation Sequencing (NGS) targeted to multigene panels/Whole Exome Sequencing (WES) in 137 girls suspected for RTT led to the identification of a de novo variant in STXBP1 gene in four atypical RTT and two RTT-like girls. De novo pathogenic variants—one in GABRB2 and, for first time, one in GABRG2—were disclosed in classic and atypical RTT patients. Interestingly, the GABRG2 variant occurred at low rate percentage in blood and buccal swabs, reinforcing the relevance of mosaicism in neurological disorders. We confirm the role of STXBP1 in atypical RTT/RTT-like patients if early psychomotor delay and epilepsy before 2 years of age are observed, indicating its inclusion in the RTT diagnostic panel. Lastly, we report pathogenic variants in Gamma-aminobutyric acid-A (GABAa) receptors as a cause of atypical/classic RTT phenotype, in accordance with the deregulation of GABAergic pathway observed in MECP2 defective in vitro and in vivo models. Full article

(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders: From the Past Towards the Future)

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15 pages, 2754 KiB

Open AccessArticle

DNA Methylation Contributes to the Differential Expression Levels of Mecp2 in Male Mice Neurons and Astrocytes

by Vichithra R.B. Liyanage, Carl O. Olson, Robby M. Zachariah, James R. Davie and Mojgan Rastegar

Int. J. Mol. Sci. 2019, 20(8), 1845; https://doi.org/10.3390/ijms20081845 - 14 Apr 2019

Cited by 27 | Viewed by 5733

Abstract

Methyl CpG binding protein-2 (MeCP2) isoforms (E1 and E2) are important epigenetic regulators in brain cells. Accordingly, MeCP2 loss- or gain-of-function mutation causes neurodevelopmental disorders, including Rett syndrome (RTT), MECP2 duplication syndrome (MDS), and autism spectrum disorders (ASD). Within different types of brain cells, highest MeCP2 levels are detected in neurons and the lowest in astrocytes. However, our current knowledge of Mecp2/MeCP2 regulatory mechanisms remains largely elusive. It appears that there is a sex-dependent effect in X-linked MeCP2-associated disorders, as RTT primarily affects females, whereas MDS is found almost exclusively in males. This suggests that Mecp2 expression levels in brain cells might be sex-dependent. Here, we investigated the sex- and cell type-specific expression of Mecp2 isoforms in male and female primary neurons and astrocytes isolated from the murine forebrain. Previously, we reported that DNA methylation of six Mecp2 regulatory elements correlated with Mecp2 levels in the brain. We now show that in male brain cells, DNA methylation is significantly correlated with the transcript expression of these two isoforms. We show that both Mecp2 isoforms are highly expressed in male neurons compared to male astrocytes, with Mecp2e1 expressed at higher levels than Mecp2e2. Our data indicate that higher DNA methylation at the Mecp2 regulatory element(s) is associated with lower levels of Mecp2 isoforms in male astrocytes compared to male neurons. Full article

(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders: From the Past Towards the Future)

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Review

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17 pages, 952 KiB

Open AccessReview

Rett Syndrome and CDKL5 Deficiency Disorder: From Bench to Clinic

by Shilpa D. Kadam, Brennan J. Sullivan, Archita Goyal, Mary E. Blue and Constance Smith-Hicks

Int. J. Mol. Sci. 2019, 20(20), 5098; https://doi.org/10.3390/ijms20205098 - 15 Oct 2019

Cited by 25 | Viewed by 6919

Abstract

Rett syndrome (RTT) and CDKL5 deficiency disorder (CDD) are two rare X-linked developmental brain disorders with overlapping but distinct phenotypic features. This review examines the impact of loss of methyl-CpG-binding protein 2 (MeCP2) and cyclin-dependent kinase-like 5 (CDKL5) on clinical phenotype, deficits in synaptic- and circuit-homeostatic mechanisms, seizures, and sleep. In particular, we compare the overlapping and contrasting features between RTT and CDD in clinic and in preclinical studies. Finally, we discuss lessons learned from recent clinical trials while reviewing the findings from pre-clinical studies. Full article

(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders: From the Past Towards the Future)

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17 pages, 716 KiB

Open AccessReview

MeCP2: A Critical Regulator of Chromatin in Neurodevelopment and Adult Brain Function

by Kubra Gulmez Karaca, David V.C. Brito and Ana M.M. Oliveira

Int. J. Mol. Sci. 2019, 20(18), 4577; https://doi.org/10.3390/ijms20184577 - 16 Sep 2019

Cited by 38 | Viewed by 8880

Abstract

Methyl CpG binding protein 2 (MeCP2) was first identified as a nuclear protein with a transcriptional repressor role that recognizes DNA methylation marks. MeCP2 has a well-established function in neurodevelopment, as evidenced by the severe neurological impairments characteristic of the Rett syndrome (RTT) pathology and the MeCP2 duplication syndrome (MDS), caused by loss or gain of MeCP2 function, respectively. Research aimed at the underlying pathophysiological mechanisms of RTT and MDS has significantly advanced our understanding of MeCP2 functions in the nervous system. It has revealed, however, that MeCP2 has more varied and complex roles than previously thought. Here we review recent insights into the functions of MeCP2 in neurodevelopment and the less explored requirement for MeCP2 in adult brain function. We focus on the emerging view that MeCP2 is a global chromatin organizer. Finally, we discuss how the individual functions of MeCP2 in neurodevelopment and adulthood are linked to its role as a chromatin regulator. Full article

(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders: From the Past Towards the Future)

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19 pages, 2493 KiB

Open AccessReview

by Lee-Chin Wong, Shekhar Singh, Hsin-Pei Wang, Chia-Jui Hsu, Su-Ching Hu and Wang-Tso Lee

Int. J. Mol. Sci. 2019, 20(17), 4176; https://doi.org/10.3390/ijms20174176 - 26 Aug 2019

Cited by 39 | Viewed by 8072

Abstract

Individuals with mutations in forkhead box G1 (FOXG1) belong to a distinct clinical entity, termed “FOXG1-related encephalopathy”. There are two clinical phenotypes/syndromes identified in FOXG1-related encephalopathy, duplications and deletions/intragenic mutations. In children with deletions or intragenic mutations of FOXG1, the recognized clinical features include microcephaly, developmental delay, severe cognitive disabilities, early-onset dyskinesia and hyperkinetic movements, stereotypies, epilepsy, and cerebral malformation. In contrast, children with duplications of FOXG1 are typically normocephalic and have normal brain magnetic resonance imaging. They also have different clinical characteristics in terms of epilepsy, movement disorders, and neurodevelopment compared with children with deletions or intragenic mutations. FOXG1 is a transcriptional factor. It is expressed mainly in the telencephalon and plays a pleiotropic role in the development of the brain. It is a key player in development and territorial specification of the anterior brain. In addition, it maintains the expansion of the neural proliferating pool, and also regulates the pace of neocortical neuronogenic progression. It also facilitates cortical layer and corpus callosum formation. Furthermore, it promotes dendrite elongation and maintains neural plasticity, including dendritic arborization and spine densities in mature neurons. In this review, we summarize the clinical features, molecular genetics, and possible pathogenesis of FOXG1-related syndrome. Full article

(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders: From the Past Towards the Future)

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13 pages, 949 KiB

Open AccessReview

Rett Syndrome and Other Neurodevelopmental Disorders Share Common Changes in Gut Microbial Community: A Descriptive Review

by Elisa Borghi and Aglaia Vignoli

Int. J. Mol. Sci. 2019, 20(17), 4160; https://doi.org/10.3390/ijms20174160 - 26 Aug 2019

Cited by 20 | Viewed by 12367

Abstract

In this narrative review, we summarize recent pieces of evidence of the role of microbiota alterations in Rett syndrome (RTT). Neurological problems are prominent features of the syndrome, but the pathogenic mechanisms modulating its severity are still poorly understood. Gut microbiota was recently demonstrated to be altered both in animal models and humans with different neurodevelopmental disorders and/or epilepsy. By investigating gut microbiota in RTT cohorts, a less rich microbial community was identified which was associated with alterations of fecal microbial short-chain fatty acids. These changes were positively correlated with severe clinical outcomes. Indeed, microbial metabolites can play a crucial role both locally and systemically, having dynamic effects on host metabolism and gene expression in many organs. Similar alterations were found in patients with autism and down syndrome as well, suggesting a potential common pathway of gut microbiota involvement in neurodevelopmental disorders. Full article

(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders: From the Past Towards the Future)

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18 pages, 2706 KiB

Open AccessReview

Microtubules: A Key to Understand and Correct Neuronal Defects in CDKL5 Deficiency Disorder?

by Isabella Barbiero, Roberta De Rosa and Charlotte Kilstrup-Nielsen

Int. J. Mol. Sci. 2019, 20(17), 4075; https://doi.org/10.3390/ijms20174075 - 21 Aug 2019

Cited by 12 | Viewed by 7065

Abstract

CDKL5 deficiency disorder (CDD) is a severe neurodevelopmental encephalopathy caused by mutations in the X-linked CDKL5 gene that encodes a serine/threonine kinase. CDD is characterised by the early onset of seizures and impaired cognitive and motor skills. Loss of CDKL5 in vitro and in vivo affects neuronal morphology at early and late stages of maturation, suggesting a link between CDKL5 and the neuronal cytoskeleton. Recently, various microtubule (MT)-binding proteins have been identified as interactors of CDKL5, indicating that its roles converge on regulating MT functioning. MTs are dynamic structures that are important for neuronal morphology, migration and polarity. The delicate control of MT dynamics is fundamental for proper neuronal functions, as evidenced by the fact that aberrant MT dynamics are involved in various neurological disorders. In this review, we highlight the link between CDKL5 and MTs, discussing how CDKL5 deficiency may lead to deranged neuronal functions through aberrant MT dynamics. Finally, we discuss whether the regulation of MT dynamics through microtubule-targeting agents may represent a novel strategy for future pharmacological approaches in the CDD field. Full article

(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders: From the Past Towards the Future)

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17 pages, 1018 KiB

Open AccessReview

Genetic Landscape of Rett Syndrome Spectrum: Improvements and Challenges

by Silvia Vidal, Clara Xiol, Ainhoa Pascual-Alonso, M. O’Callaghan, Mercè Pineda and Judith Armstrong

Int. J. Mol. Sci. 2019, 20(16), 3925; https://doi.org/10.3390/ijms20163925 - 12 Aug 2019

Cited by 33 | Viewed by 7699

Abstract

Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that primarily affects females, resulting in severe cognitive and physical disabilities, and is one of the most prevalent causes of intellectual disability in females. More than fifty years after the first publication on Rett syndrome, and almost two decades since the first report linking RTT to the MECP2 gene, the research community’s effort is focused on obtaining a better understanding of the genetics and the complex biology of RTT and Rett-like phenotypes without MECP2 mutations. Herein, we review the current molecular genetic studies, which investigate the genetic causes of RTT or Rett-like phenotypes which overlap with other genetic disorders and document the swift evolution of the techniques and methodologies employed. This review also underlines the clinical and genetic heterogeneity of the Rett syndrome spectrum and provides an overview of the RTT-related genes described to date, many of which are involved in epigenetic gene regulation, neurotransmitter action or RNA transcription/translation. Finally, it discusses the importance of including both phenotypic and genetic diagnosis to provide proper genetic counselling from a patient’s perspective and the appropriate treatment. Full article

(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders: From the Past Towards the Future)

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18 pages, 266 KiB

Open AccessReview

Glial Dysfunction in MeCP2 Deficiency Models: Implications for Rett Syndrome

by Uri Kahanovitch, Kelsey C. Patterson, Raymundo Hernandez and Michelle L. Olsen

Int. J. Mol. Sci. 2019, 20(15), 3813; https://doi.org/10.3390/ijms20153813 - 05 Aug 2019

Cited by 30 | Viewed by 4434

Abstract

Rett syndrome (RTT) is a rare, X-linked neurodevelopmental disorder typically affecting females, resulting in a range of symptoms including autistic features, intellectual impairment, motor deterioration, and autonomic abnormalities. RTT is primarily caused by the genetic mutation of the Mecp2 gene. Initially considered a neuronal disease, recent research shows that glial dysfunction contributes to the RTT disease phenotype. In the following manuscript, we review the evidence regarding glial dysfunction and its effects on disease etiology. Full article

(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders: From the Past Towards the Future)

14 pages, 683 KiB

Open AccessReview

Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome

by Marco Segatto, Claudia Tonini, Frank W. Pfrieger, Viviana Trezza and Valentina Pallottini

Int. J. Mol. Sci. 2019, 20(13), 3317; https://doi.org/10.3390/ijms20133317 - 05 Jul 2019

Cited by 35 | Viewed by 5608

Abstract

The mevalonate (MVA)/cholesterol pathway is crucial for central nervous system (CNS) development and function and consequently, any dysfunction of this fundamental metabolic pathway is likely to provoke pathologic changes in the brain. Mutations in genes directly involved in MVA/cholesterol metabolism cause a range of diseases, many of which present neurologic and psychiatric symptoms. This raises the question whether other diseases presenting similar symptoms are related albeit indirectly to the MVA/cholesterol pathway. Here, we summarized the current literature suggesting links between MVA/cholesterol dysregulation and specific diseases, namely autism spectrum disorder and 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)

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