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Fragile X Syndrome: Molecular Mechanisms, Cellular and Animal Models, and...
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Fragile X Syndrome: Molecular Mechanisms, Cellular and Animal Models, and Targeted Therapeutics

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (1 March 2022) | Viewed by 25014

Special Issue Editors

Dr. Rob Willemsen

E-Mail Website
Guest Editor
Department of Clinical Genetics, Erasmus Medical Center DR Rotterdam, Rotterdam, The Netherlands
Interests: diseases of unstable repeat expansion; including fragile X syndrome; FXTAS and C9ORF72-linked FTD/ALS
Dr. Frank Kooy

E-Mail Website
Guest Editor
Department of Medical Genetics, Universiteit Antwerpen, Antwerpen, Belgium
Interests: genetics and disease mechanisms of ID and autism disorders, including the fragile X syndrome; therapies for genetic neurodevelopmental disorders

Special Issue Information

Dear Colleagues,

The discovery of the FMR1 gene as the cause of the fragile X syndrome, a frequent form of intellectual disability and autism, can be considered one of the major breakthroughs in medical genetics. A dynamic expansion of a trinucleotide CGG repeat from parent to child explained the “anticipation” in the families, e.g., the increase in the number of affected patients with generations. The neurodevelopmental disorder is caused by a full expansion of the CGG repeat accompanied by epigenetic alterations in the youngest generations.

In the three decades that passed since the gene discovery, understanding the molecular mechanisms underlying fragile X syndrome, generation of cell and animal models, and new therapeutic strategies has been the focus in fragile X syndrome research.

This Special Issue aims to provides a snapshot of our continuing search for causes and treatment of the fragile X syndrome, which has evolved as a prime example for translational research in neurodevelopmental disorders.

Dr. Rob Willemsen
Dr. Frank Kooy
Guest Editors

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Keywords

  • fragile X syndrome
  • FMR1
  • FMRP
  • CGG repeat
  • repeat instability
  • animal and cell models
  • targeted treatment

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Published Papers (7 papers)

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Research

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18 pages, 3518 KiB  
Article
Age-Dependent Dysregulation of APP in Neuronal and Skin Cells from Fragile X Individuals
by Giulia Cencelli, Laura Pacini, Anastasia De Luca, Ilenia Messia, Antonietta Gentile, Yunhee Kang, Veronica Nobile, Elisabetta Tabolacci, Peng Jin, Maria Giulia Farace and Claudia Bagni
Cells 2023, 12(5), 758; https://doi.org/10.3390/cells12050758 - 27 Feb 2023
Cited by 4 | Viewed by 2291
Abstract
Fragile X syndrome (FXS) is the most common form of monogenic intellectual disability and autism, caused by the absence of the functional fragile X messenger ribonucleoprotein 1 (FMRP). FXS features include increased and dysregulated protein synthesis, observed in both murine and human cells. [...] Read more.
Fragile X syndrome (FXS) is the most common form of monogenic intellectual disability and autism, caused by the absence of the functional fragile X messenger ribonucleoprotein 1 (FMRP). FXS features include increased and dysregulated protein synthesis, observed in both murine and human cells. Altered processing of the amyloid precursor protein (APP), consisting of an excess of soluble APPα (sAPPα), may contribute to this molecular phenotype in mice and human fibroblasts. Here we show an age-dependent dysregulation of APP processing in fibroblasts from FXS individuals, human neural precursor cells derived from induced pluripotent stem cells (iPSCs), and forebrain organoids. Moreover, FXS fibroblasts treated with a cell-permeable peptide that decreases the generation of sAPPα show restored levels of protein synthesis. Our findings suggest the possibility of using cell-based permeable peptides as a future therapeutic approach for FXS during a defined developmental window. Full article
(This article belongs to the Special Issue Fragile X Syndrome: Molecular Mechanisms, Cellular and Animal Models, and Targeted Therapeutics)
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22 pages, 1600 KiB  
Article
Effects of Soy-Based Infant Formula on Weight Gain and Neurodevelopment in an Autism Mouse Model
by Cara J. Westmark, Mikolaj J. Filon, Patricia Maina, Lauren I. Steinberg, Chrysanthy Ikonomidou and Pamela R. Westmark
Cells 2022, 11(8), 1350; https://doi.org/10.3390/cells11081350 - 15 Apr 2022
Cited by 7 | Viewed by 2937
Abstract
Mice fed soy-based diets exhibit increased weight gain compared to mice fed casein-based diets, and the effects are more pronounced in a model of fragile X syndrome (FXS; Fmr1KO). FXS is a neurodevelopmental disability characterized by intellectual impairment, seizures, autistic behavior, [...] Read more.
Mice fed soy-based diets exhibit increased weight gain compared to mice fed casein-based diets, and the effects are more pronounced in a model of fragile X syndrome (FXS; Fmr1KO). FXS is a neurodevelopmental disability characterized by intellectual impairment, seizures, autistic behavior, anxiety, and obesity. Here, we analyzed body weight as a function of mouse age, diet, and genotype to determine the effect of diet (soy, casein, and grain-based) on weight gain. We also assessed plasma protein biomarker expression and behavior in response to diet. Juvenile Fmr1KO mice fed a soy protein-based rodent chow throughout gestation and postnatal development exhibit increased weight gain compared to mice fed a casein-based purified ingredient diet or grain-based, low phytoestrogen chow. Adolescent and adult Fmr1KO mice fed a soy-based infant formula diet exhibited increased weight gain compared to reference diets. Increased body mass was due to increased lean mass. Wild-type male mice fed soy-based infant formula exhibited increased learning in a passive avoidance paradigm, and Fmr1KO male mice had a deficit in nest building. Thus, at the systems level, consumption of soy-based diets increases weight gain and affects behavior. At the molecular level, a soy-based infant formula diet was associated with altered expression of numerous plasma proteins, including the adipose hormone leptin and the β-amyloid degrading enzyme neprilysin. In conclusion, single-source, soy-based diets may contribute to the development of obesity and the exacerbation of neurological phenotypes in developmental disabilities, such as FXS. Full article
(This article belongs to the Special Issue Fragile X Syndrome: Molecular Mechanisms, Cellular and Animal Models, and Targeted Therapeutics)
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Review

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33 pages, 1770 KiB  
Review
Across Dimensions: Developing 2D and 3D Human iPSC-Based Models of Fragile X Syndrome
by Azalea Lee, Jie Xu, Zhexing Wen and Peng Jin
Cells 2022, 11(11), 1725; https://doi.org/10.3390/cells11111725 - 24 May 2022
Cited by 5 | Viewed by 3466
Abstract
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder. FXS is caused by a cytosine-guanine-guanine (CGG) trinucleotide repeat expansion in the untranslated region of the FMR1 gene leading to the functional loss of the gene’s [...] Read more.
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder. FXS is caused by a cytosine-guanine-guanine (CGG) trinucleotide repeat expansion in the untranslated region of the FMR1 gene leading to the functional loss of the gene’s protein product FMRP. Various animal models of FXS have provided substantial knowledge about the disorder. However, critical limitations exist in replicating the pathophysiological mechanisms. Human induced pluripotent stem cells (hiPSCs) provide a unique means of studying the features and processes of both normal and abnormal human neurodevelopment in large sample quantities in a controlled setting. Human iPSC-based models of FXS have offered a better understanding of FXS pathophysiology specific to humans. This review summarizes studies that have used hiPSC-based two-dimensional cellular models of FXS to reproduce the pathology, examine altered gene expression and translation, determine the functions and targets of FMRP, characterize the neurodevelopmental phenotypes and electrophysiological features, and, finally, to reactivate FMR1. We also provide an overview of the most recent studies using three-dimensional human brain organoids of FXS and end with a discussion of current limitations and future directions for FXS research using hiPSCs. Full article
(This article belongs to the Special Issue Fragile X Syndrome: Molecular Mechanisms, Cellular and Animal Models, and Targeted Therapeutics)
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18 pages, 1037 KiB  
Review
New Animal Models for Understanding FMRP Functions and FXS Pathology
by Eliza Curnow and Yuan Wang
Cells 2022, 11(10), 1628; https://doi.org/10.3390/cells11101628 - 12 May 2022
Cited by 7 | Viewed by 3239
Abstract
Fragile X encompasses a range of genetic conditions, all of which result as a function of changes within the FMR1 gene and abnormal production and/or expression of the FMR1 gene products. Individuals with Fragile X syndrome (FXS), the most common heritable form of [...] Read more.
Fragile X encompasses a range of genetic conditions, all of which result as a function of changes within the FMR1 gene and abnormal production and/or expression of the FMR1 gene products. Individuals with Fragile X syndrome (FXS), the most common heritable form of intellectual disability, have a full-mutation sequence (>200 CGG repeats) which brings about transcriptional silencing of FMR1 and loss of FMR protein (FMRP). Despite considerable progress in our understanding of FXS, safe, effective, and reliable treatments that either prevent or reduce the severity of the FXS phenotype have not been approved. While current FXS animal models contribute their own unique understanding to the molecular, cellular, physiological, and behavioral deficits associated with FXS, no single animal model is able to fully recreate the FXS phenotype. This review will describe the status and rationale in the development, validation, and utility of three emerging animal model systems for FXS, namely the nonhuman primate (NHP), Mongolian gerbil, and chicken. These developing animal models will provide a sophisticated resource in which the deficits in complex functions of perception, action, and cognition in the human disorder are accurately reflected and aid in the successful translation of novel therapeutics and interventions to the clinic setting. Full article
(This article belongs to the Special Issue Fragile X Syndrome: Molecular Mechanisms, Cellular and Animal Models, and Targeted Therapeutics)
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45 pages, 2162 KiB  
Review
Towards Kinase Inhibitor Therapies for Fragile X Syndrome: Tweaking Twists in the Autism Spectrum Kinase Signaling Network
by Claudio D’Incal, Jitse Broos, Thierry Torfs, R. Frank Kooy and Wim Vanden Berghe
Cells 2022, 11(8), 1325; https://doi.org/10.3390/cells11081325 - 13 Apr 2022
Cited by 10 | Viewed by 4727
Abstract
Absence of the Fragile X Messenger Ribonucleoprotein 1 (FMRP) causes autism spectrum disorders and intellectual disability, commonly referred to as the Fragile X syndrome. FMRP is a negative regulator of protein translation and is essential for neuronal development and synapse formation. FMRP is [...] Read more.
Absence of the Fragile X Messenger Ribonucleoprotein 1 (FMRP) causes autism spectrum disorders and intellectual disability, commonly referred to as the Fragile X syndrome. FMRP is a negative regulator of protein translation and is essential for neuronal development and synapse formation. FMRP is a target for several post-translational modifications (PTMs) such as phosphorylation and methylation, which tightly regulate its cellular functions. Studies have indicated the involvement of FMRP in a multitude of cellular pathways, and an absence of FMRP was shown to affect several neurotransmitter receptors, for example, the GABA receptor and intracellular signaling molecules such as Akt, ERK, mTOR, and GSK3. Interestingly, many of these molecules function as protein kinases or phosphatases and thus are potentially amendable by pharmacological treatment. Several treatments acting on these kinase-phosphatase systems have been shown to be successful in preclinical models; however, they have failed to convincingly show any improvements in clinical trials. In this review, we highlight the different protein kinase and phosphatase studies that have been performed in the Fragile X syndrome. In our opinion, some of the paradoxical study conclusions are potentially due to the lack of insight into integrative kinase signaling networks in the disease. Quantitative proteome analyses have been performed in several models for the FXS to determine global molecular processes in FXS. However, only one phosphoproteomics study has been carried out in Fmr1 knock-out mouse embryonic fibroblasts, and it showed dysfunctional protein kinase and phosphatase signaling hubs in the brain. This suggests that the further use of phosphoproteomics approaches in Fragile X syndrome holds promise for identifying novel targets for kinase inhibitor therapies. Full article
(This article belongs to the Special Issue Fragile X Syndrome: Molecular Mechanisms, Cellular and Animal Models, and Targeted Therapeutics)
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Other

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5 pages, 219 KiB  
Comment
Comment on Herring et al. The Use of “Retardation” in FRAXA, FMRP, FMR1 and Other Designations. Cells 2022, 11, 1044
by Elspeth Bruford and on behalf of the HUGO Gene Nomenclature Committee (HGNC)
Cells 2022, 11(12), 1937; https://doi.org/10.3390/cells11121937 - 16 Jun 2022
Cited by 3 | Viewed by 1781
Abstract
This commentary is written in response to the recent article from Herring et al., discussing the eradication of the offensive term “retardation” from gene nomenclature. We discuss the work of the HUGO (Human Genome Organisation) Gene Nomenclature Committee (HGNC) and outline the steps [...] Read more.
This commentary is written in response to the recent article from Herring et al., discussing the eradication of the offensive term “retardation” from gene nomenclature. We discuss the work of the HUGO (Human Genome Organisation) Gene Nomenclature Committee (HGNC) and outline the steps already taken to remove this term from our gene names. We also highlight the latest nomenclature changes made as a result of discussions with the authors and agreement with the European Fragile X Network. Full article
(This article belongs to the Special Issue Fragile X Syndrome: Molecular Mechanisms, Cellular and Animal Models, and Targeted Therapeutics)
7 pages, 229 KiB  
Opinion
The Use of “Retardation” in FRAXA, FMRP, FMR1 and Other Designations
by Jonathan Herring, Kirsten Johnson and Jörg Richstein
Cells 2022, 11(6), 1044; https://doi.org/10.3390/cells11061044 - 19 Mar 2022
Cited by 13 | Viewed by 5379
Abstract
The European Fragile X Network met in Wroclaw, Poland, November 2021, and agreed to work towards the eradication of the word “retardation” in regard to the naming of the fragile X gene (FRAXA) and protein (FMRP). There are further genes which have “retardation” [...] Read more.
The European Fragile X Network met in Wroclaw, Poland, November 2021, and agreed to work towards the eradication of the word “retardation” in regard to the naming of the fragile X gene (FRAXA) and protein (FMRP). There are further genes which have “retardation” or abbreviations for “retardation” in their names or full designations, including FMR1, FMR2, FXR1, FXR2, NUFIP1, AFF1, CYFIP1, etc. “Retardation” was commonly used as a term in years past, but now any reference, even in an abbreviation, is offensive. This article discusses the stigmatisation associated with “retardation”, which leads to discrimination; the inaccuracy of using “retardation” in these designations; and the breadth of fragile X syndrome being beyond that of neurodiversity. A more inclusive terminology is called for, one which ceases to use any reference to “retardation”. Precedents for offensive gene names being altered is set out. The proposal is to approach the HGNC (HUGO [Human Genome Organisation] Gene Nomenclature Committee) for new terminology to be enacted. Ideas from other researchers in the field are welcomed. Full article
(This article belongs to the Special Issue Fragile X Syndrome: Molecular Mechanisms, Cellular and Animal Models, and Targeted Therapeutics)
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