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Current Molecular Science of Fragile X Syndrome and Associated Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 30 June 2025 | Viewed by 11842

Special Issue Editors


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Guest Editor
1. Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, UC Davis Health, Sacramento, CA, USA
2. Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, USA
Interests: neurodevelopmental disorders including fragile X (FMR1) gene and related conditions
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, Department of Pediatrics, UC Davis Health, Sacramento, CA, USA
Interests: fragile X syndrome (FXS); autism (ASD), and other neurodevelopmental disorders

Special Issue Information

Dear Colleagues,

This special issue titled “Current Molecular Science of Fragile X Syndrome and Associated Disorders” will be edited by Flora Tassone PhD and Randi Hagerman MD, both from the MIND Institute at University of California Davis Medical Center. It will cover advances in our understanding of molecular pathways that underlie fragile X syndrome and premutation disorders. Animal, cellular, and human studies will be highlighted. Phenotype research as it relates to the molecular basis are encouraged. Biomarker studies and gene therapy studies are welcome. Basic research, translational research and the results of clinical trials are welcome. We are interested in original research, reviews and even case reports for this special issue in IJMS.

Prof. Dr. Flora Tassone
Prof. Dr. Randi Hagerman
Guest Editors

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Keywords

  • FMR1
  • fragile X syndrome
  • FXPOI
  • FXTAS
  • FXAND
  • FXPAC
  • molecular studies

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Published Papers (12 papers)

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Research

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19 pages, 2427 KiB  
Article
Beyond Repetition: The Role of Gray Zone Alleles in the Upregulation of FMR1-Binding miR-323a-3p and the Modification of BMP/SMAD-Pathway Gene Expression in Human Granulosa Cells
by Adriana Vilkaite, Xuan Phuoc Nguyen, Cansu Türkan Güzel, Lucas Gottschlich, Ulrike Bender, Jens E. Dietrich, Katrin Hinderhofer, Thomas Strowitzki and Julia Rehnitz
Int. J. Mol. Sci. 2025, 26(7), 3192; https://doi.org/10.3390/ijms26073192 - 29 Mar 2025
Viewed by 390
Abstract
The Fragile X mental retardation type 1 gene (FMR1) contains a CGG triplet cluster of varied length (30 repeats on average) located in its 5′ UTR. In its premutated state (54–200 repeats), FMR1 contributes to the pathogenesis of premature ovarian insufficiency [...] Read more.
The Fragile X mental retardation type 1 gene (FMR1) contains a CGG triplet cluster of varied length (30 repeats on average) located in its 5′ UTR. In its premutated state (54–200 repeats), FMR1 contributes to the pathogenesis of premature ovarian insufficiency (POI). Its gray zone alleles (41–54 repeats) are supposed to impair the ovarian function as well. In the case of a CGG repeat length > 200, Fragile X syndrome occurs. Post-transcriptional expression of FMR1 is regulated by microRNAs. Although miR-323a-3p overexpression suppresses FMR1 in various tissues, this relationship has not been evaluated in the human ovary. Additionally, this microRNA targets SMADs, which are suggested regulators of ovarian cell proliferation, growth, and function. This study investigated how FMR1 allele lengths with CGG repeat numbers n < 55 (normal and gray zone genotypes) relate to miR-323a-3p expression and how they may impact associated SMAD expression in human granulosa cells. COV434 cells and patient-derived GCs were used to evaluate FMR1, miR-323a-3p, and BMP/SMAD-pathway member expression levels. Briefly, miR-323a-3p was significantly upregulated in GCs of the gray zone group compared to the normal allele group (p < 0.0001), while the FMR1 level did not vary. Furthermore, the gray zone group showed a significant upregulation of BMPR2, SMAD1, SMAD4, and SMAD9. In contrast, the miR-323a-3p transfection of COV434 cells significantly downregulated SMAD3, SMAD4, SMAD5, and SMAD9, while the FMR1 and SMAD1 levels remained stable. Our findings highlight a CGG repeat number-dependent upregulation of miR-323a-3p and an alteration of the BMP/SMAD pathway, suggesting that these changes happen and contribute to impaired ovarian function independently. Full article
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13 pages, 1317 KiB  
Article
In Utero Alcohol and Unsuitable Home Environmental Exposure Combined with FMR1 Full Mutation Allele Cause Severe Fragile X Syndrome Phenotypes
by Tri Indah Winarni, Ramkumar Aishworiya, Hannah Culpepper, Marwa Zafarullah, Guadalupe Mendoza, Tanaporn Jasmine Wilaisakditipakorn, Narueporn Likhitweerawong, Julie Law, Randi Hagerman and Flora Tassone
Int. J. Mol. Sci. 2025, 26(7), 2840; https://doi.org/10.3390/ijms26072840 - 21 Mar 2025
Viewed by 372
Abstract
We investigated the molecular and clinical profile of five boys carrying the fragile X messenger ribonucleoprotein 1 (FMR1) mutation and who suffered from the effects of prenatal alcohol exposure. Fragile X syndrome (FXS) testing was performed using PCR and Southern Blot [...] Read more.
We investigated the molecular and clinical profile of five boys carrying the fragile X messenger ribonucleoprotein 1 (FMR1) mutation and who suffered from the effects of prenatal alcohol exposure. Fragile X syndrome (FXS) testing was performed using PCR and Southern Blot analysis, and fragile X messenger ribonucleoprotein protein (FMRP) expression levels were measured by Western blot analysis. Clinical evaluation included cognitive functions, adaptive skills, autism phenotype, and severity of behavior measures. Fetal Alcohol Spectrum Disorder (FASD) was also assessed. Five adopted male siblings were investigated, four of which (cases 1, 2, 3, and 4) were diagnosed with FXS, FASD, and ASD, and one, the fraternal triplet (case 5), was diagnosed with FASD and ASD and no FXS. The molecular profile of case 1 and 2 showed the presence of a hypermethylated full mutation (FM) and the resulting absence of FMRP. Cases 3 and 4 (identical twins) were FM-size mosaics (for the presence of an FM and a deleted allele), resulting in 16% and 50% FMRP expression levels, respectively. FMRP expression level was normal in case 5 (fraternal twin). Severe behavioral problems were observed in all cases, including aggression, tantrum, self-harming, anxiety, and defiant behavior, due to different mutations of the FMR1 gene, in addition to biological exposure, home environmental factors, and potentially to additional background gene effects. Full article
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15 pages, 2290 KiB  
Article
Tissue-Specific Effects of the DNA Helicase FANCJ/BRIP1/BACH1 on Repeat Expansion in a Mouse Model of the Fragile X-Related Disorders
by Diego Antonio Jimenez, Alexandra Walker, Karen Usdin and Xiaonan Zhao
Int. J. Mol. Sci. 2025, 26(6), 2655; https://doi.org/10.3390/ijms26062655 - 15 Mar 2025
Viewed by 553
Abstract
Fragile X-related disorders (FXDs) are caused by the expansion of a CGG repeat tract in the 5’-UTR of the FMR1 gene. The expansion mechanism is likely shared with the 45+ other human diseases resulting from repeat expansion, a process that has been shown [...] Read more.
Fragile X-related disorders (FXDs) are caused by the expansion of a CGG repeat tract in the 5’-UTR of the FMR1 gene. The expansion mechanism is likely shared with the 45+ other human diseases resulting from repeat expansion, a process that has been shown to require key mismatch repair (MMR) factors. FANCJ, a DNA helicase involved in unwinding unusual DNA secondary structures, has been implicated in a number of DNA repair processes including MMR. To test the role of FANCJ in repeat expansion, we crossed FancJ-null mice to an FXD mouse model. We found that loss of FANCJ resulted in a trend towards more extensive expansion that was significant for the small intestine and male germline. This finding has interesting implications for the expansion mechanism and raises the possibility that other DNA helicases may be important modifiers of expansion risk in certain cell types. Full article
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19 pages, 1277 KiB  
Article
Prosodic Differences in Women with the FMR1 Premutation: Subtle Expression of Autism-Related Phenotypes Through Speech
by Joseph C. Y. Lau, Janna Guilfoyle, Stephanie Crawford, Grace Johnson, Emily Landau, Jiayin Xing, Mitra Kumareswaran, Sarah Ethridge, Maureen Butler, Lindsay Goldman, Gary E. Martin, Lili Zhou, Jennifer Krizman, Trent Nicol, Nina Kraus, Elizabeth Berry-Kravis and Molly Losh
Int. J. Mol. Sci. 2025, 26(6), 2481; https://doi.org/10.3390/ijms26062481 - 11 Mar 2025
Viewed by 461
Abstract
Evidence suggests that carriers of FMR1 mutations (e.g., fragile X syndrome and the FMR1 premutation) may demonstrate specific phenotypic patterns shared with autism (AU), particularly in the domain of pragmatic language, which involves the use of language in social contexts. Such evidence may [...] Read more.
Evidence suggests that carriers of FMR1 mutations (e.g., fragile X syndrome and the FMR1 premutation) may demonstrate specific phenotypic patterns shared with autism (AU), particularly in the domain of pragmatic language, which involves the use of language in social contexts. Such evidence may implicate FMR1, a high-confidence gene associated with AU, in components of the AU phenotype. Prosody (i.e., using intonation and rhythm in speech to express meaning) is a pragmatic feature widely impacted in AU. Prosodic differences have also been observed in unaffected relatives of autistic individuals and in those with fragile X syndrome, although prosody has not been extensively studied among FMR1 premutation carriers. This study investigated how FMR1 variability may specifically influence prosody by examining the prosodic characteristics and related neural processing of prosodic features in women carrying the FMR1 premutation (PM). In Study 1, acoustic measures of prosody (i.e., in intonation and rhythm) were examined in speech samples elicited from a semi-structured narrative task. Study 2 examined the neural frequency following response (FFR) as an index of speech prosodic processing. Findings revealed differences in the production of intonation and rhythm in PM carriers relative to controls, with patterns that parallel differences identified in parents of autistic individuals. No differences in neural processing of prosodic cues were found. Post hoc analyses further revealed associations between speech rhythm and FMR1 variation (number of CGG repeats) among PM carriers. Together, the results suggest that FMR1 may play a role in speech prosodic phenotypes, at least in speech production, contributing to a deeper understanding of AU-related speech and language phenotypes among FMR1 mutation carriers. Full article
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14 pages, 1246 KiB  
Article
Reduced Respiratory Sinus Arrhythmia in Infants with the FMR1 Premutation
by Abigail Chase, Lisa Hamrick, Holley Arnold, Jenna Smith, Rachel Hantman, Kaitlyn Cortez, Tatyana Adayev, Nicole D. Tortora, Alison Dahlman and Jane Roberts
Int. J. Mol. Sci. 2025, 26(5), 2186; https://doi.org/10.3390/ijms26052186 - 28 Feb 2025
Viewed by 430
Abstract
The fragile X premutation (FXpm) is caused by a CGG repeat expansion on the FMR1 gene. In adults, FXpm is linked with autonomic nervous system (ANS) dysfunction and impairment is associated with CGG repeat length. Given scant infancy research, we examined ANS functioning, [...] Read more.
The fragile X premutation (FXpm) is caused by a CGG repeat expansion on the FMR1 gene. In adults, FXpm is linked with autonomic nervous system (ANS) dysfunction and impairment is associated with CGG repeat length. Given scant infancy research, we examined ANS functioning, via respiratory sinus arrhythmia (RSA) and interbeat interval (IBI), in 82 FXpm and neurotypical infants and their associations with CGG repeats. FXpm infants exhibited lower RSA but no IBI differences. There were no associations between ANS functioning and CGG repeat length. These findings identify an ANS biomarker consistent with the emerging pediatric phenotype in FXpm. Full article
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13 pages, 2808 KiB  
Article
Nigrostriatal Degeneration Underpins Sensorimotor Dysfunction in an Inducible Mouse Model of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)
by Emre Kul, Mónica Santos and Oliver Stork
Int. J. Mol. Sci. 2025, 26(4), 1511; https://doi.org/10.3390/ijms26041511 - 11 Feb 2025
Viewed by 657
Abstract
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by moderately expanded CGG trinucleotide repeats in the 5′ untranslated region (UTR) of the FMR1 gene. Characterized by motor deficits such as action tremor and cerebellar gait ataxia, FXTAS is further distinguished [...] Read more.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by moderately expanded CGG trinucleotide repeats in the 5′ untranslated region (UTR) of the FMR1 gene. Characterized by motor deficits such as action tremor and cerebellar gait ataxia, FXTAS is further distinguished by ubiquitin-positive intranuclear inclusions in neurons and glia. However, its clinical spectrum often overlaps with other neurodegenerative conditions such as Parkinson’s disease (PD). Sensorimotor gating deficits, commonly associated with disorders affecting the nigrostriatal pathway such as PD, have been reported in FXTAS, but the underlying connection between these two phenotypes remains undetermined. In this study, we used the P90CGG mouse model of FXTAS, which expresses 90 CGG repeats upon doxycycline induction, to investigate sensorimotor gating deficits and their relationship to nigrostriatal degeneration. After induction, the P90CGG model exhibited late-onset impairments in prepulse inhibition (PPI), a cross-species measure of sensorimotor gating. These deficits coincided with pronounced nigrostriatal degeneration but occurred without evidence of inclusion formation in the substantia nigra. Our findings highlight nigrostriatal degeneration, which has not previously been reported in animal models of FXTAS, and suggest a potential link to sensorimotor gating dysfunction within the context of the disorder. Full article
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14 pages, 1572 KiB  
Article
Ascorbic Acid Ameliorates Molecular and Developmental Defects in Human-Induced Pluripotent Stem Cell and Cerebral Organoid Models of Fragile X Syndrome
by Keith M. Gunapala, Aseel Gadban, Faiza Noreen, Primo Schär, Nissim Benvenisty and Verdon Taylor
Int. J. Mol. Sci. 2024, 25(23), 12718; https://doi.org/10.3390/ijms252312718 - 26 Nov 2024
Viewed by 1195
Abstract
Fragile X Syndrome (FX) is the most common form of inherited cognitive impairment and falls under the broader category of Autism Spectrum Disorders (ASD). FX is caused by a CGG trinucleotide repeat expansion in the non-coding region of the X-linked Fragile X Messenger [...] Read more.
Fragile X Syndrome (FX) is the most common form of inherited cognitive impairment and falls under the broader category of Autism Spectrum Disorders (ASD). FX is caused by a CGG trinucleotide repeat expansion in the non-coding region of the X-linked Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, leading to its hypermethylation and epigenetic silencing. Animal models of FX rely on the deletion of the Fmr1 gene, which fails to replicate the epigenetic silencing mechanism of the FMR1 gene observed in human patients. Human stem cells carrying FX repeat expansions have provided a better understanding of the basis of epigenetic silencing of FMR1. Previous studies have found that 5-Azacytidine (5Azac) can reverse this methylation; however, 5Azac can be toxic, which may limit its therapeutic potential. Here, we show that the dietary factor Ascorbic Acid (AsA) can reduce DNA methylation in the FMR1 locus and lead to an increase in FMR1 gene expression in FX iPSCs and cerebral organoids. In addition, AsA treatment rescued neuronal gene expression and morphological defects observed in FX iPSC-derived cerebral organoids. Hence, we demonstrate that the dietary co-factor AsA can partially revert the molecular and morphological defects seen in human FX models in vitro. Our findings have implications for the development of novel therapies for FX in the future. Full article
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13 pages, 534 KiB  
Article
Apolipoproteine and KLOTHO Gene Variants Do Not Affect the Penetrance of Fragile X-Associated Tremor/Ataxia Syndrome
by Tri Indah Winarni, Ye Hyun Hwang, Susan M. Rivera, David Hessl, Blythe P. Durbin-Johnson, Agustini Utari, Randi Hagerman and Flora Tassone
Int. J. Mol. Sci. 2024, 25(15), 8103; https://doi.org/10.3390/ijms25158103 - 25 Jul 2024
Viewed by 995
Abstract
In this study, the potential role and interaction of the APOε and KLOTHO genes on the penetrance of fragile X-associated tremor/ataxia syndrome (FXTAS) and on the IQ trajectory were investigated. FXTAS was diagnosed based on molecular, clinical and radiological criteria. Males with the [...] Read more.
In this study, the potential role and interaction of the APOε and KLOTHO genes on the penetrance of fragile X-associated tremor/ataxia syndrome (FXTAS) and on the IQ trajectory were investigated. FXTAS was diagnosed based on molecular, clinical and radiological criteria. Males with the premutation (PM) over 50 years, 165 with and 34 without an FXTAS diagnosis, were included in this study and were compared based on their APO (ε2-ε3-ε4) and KLOTHO variant (KL-VS) genotypes. The effect of APOε4 on FXTAS stage and on diagnosis did not differ significantly by KL-VS genotype with interaction effect p = 0.662 and p = 0.91, respectively. In the FXTAS individuals with an APOε2 allele, a marginal significance was observed towards a larger decline in verbal IQ (VIQ) in individuals with an APOε4 allele compared to those without an APOε4 allele (p = 0.071). In conclusion, our findings suggest that the APOε4 and KL-VS genotypes alone or through their interaction effect do not appear to predispose to either FXTAS diagnosis or stage in male carriers of the PM allele. A further study is needed to establish the trend of IQ decline in the FXTAS individuals who carry APOε4 with APOε2 compared to those without APOε4. Full article
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16 pages, 3018 KiB  
Article
Circadian Rhythm and Sleep Analyses in a Fruit Fly Model of Fragile X Syndrome Using a Video-Based Automated Behavioral Research System
by Sara Milojevic, Arijit Ghosh, Vedrana Makevic, Maja Stojkovic, Maria Capovilla, Tomislav Tosti, Dejan Budimirovic and Dragana Protic
Int. J. Mol. Sci. 2024, 25(14), 7949; https://doi.org/10.3390/ijms25147949 - 20 Jul 2024
Cited by 1 | Viewed by 2495
Abstract
Fragile X syndrome (FXS) is caused by the full mutation in the FMR1 gene on the Xq27.3 chromosome region. It is the most common monogenic cause of autism spectrum disorder (ASD) and inherited intellectual disability (ID). Besides ASD and ID and other symptoms, [...] Read more.
Fragile X syndrome (FXS) is caused by the full mutation in the FMR1 gene on the Xq27.3 chromosome region. It is the most common monogenic cause of autism spectrum disorder (ASD) and inherited intellectual disability (ID). Besides ASD and ID and other symptoms, individuals with FXS may exhibit sleep problems and impairment of circadian rhythm (CR). The Drosophila melanogaster models of FXS, such as dFMR1B55, represent excellent models for research in the FXS field. During this study, sleep patterns and CR in dFMR1B55 mutants were analyzed, using a new platform based on continuous high-resolution videography integrated with a highly-customized version of an open-source software. This methodology provides more sensitive results, which could be crucial for all further research in this model of fruit flies. The study revealed that dFMR1B55 male mutants sleep more and can be considered weak rhythmic flies rather than totally arrhythmic and present a good alternative animal model of genetic disorder, which includes impairment of CR and sleep behavior. The combination of affordable videography and software used in the current study is a significant improvement over previous methods and will enable broader adaptation of such high-resolution behavior monitoring methods. Full article
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Review

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16 pages, 847 KiB  
Review
Therapeutic Effects of Pharmacological Modulation of Serotonin Brain System in Human Patients and Animal Models of Fragile X Syndrome
by Lucia Ciranna and Lara Costa
Int. J. Mol. Sci. 2025, 26(6), 2495; https://doi.org/10.3390/ijms26062495 - 11 Mar 2025
Viewed by 508
Abstract
The brain serotonin (5-HT) system modulates glutamatergic and GABAergic transmission in almost every brain area, crucially regulating mood, food intake, body temperature, pain, hormone secretion, learning and memory. Previous studies suggest a disruption of the brain 5-HT system in Fragile X Syndrome, with [...] Read more.
The brain serotonin (5-HT) system modulates glutamatergic and GABAergic transmission in almost every brain area, crucially regulating mood, food intake, body temperature, pain, hormone secretion, learning and memory. Previous studies suggest a disruption of the brain 5-HT system in Fragile X Syndrome, with abnormal activity of the 5-HT transporter leading to altered 5-HT brain levels. We provide an update on therapeutic effects exerted by drugs modulating serotonergic transmission on Fragile X patients and animal models. The enhancement of serotonergic transmission using Selective Serotonin Reuptake Inhibitors (SSRIs) corrected mood disorders and language deficits in Fragile X patients. In Fmr1 KO mice, a model of Fragile X Syndrome, selective 5-HT7 receptor agonists rescued synaptic plasticity, memory and stereotyped behavior. In addition, drugs specifically acting on 5-HT1A, 5-HT2 and 5-HT5 receptor subtypes were able to correct, respectively, epilepsy, learning deficits and hyperactivity in different Fragile X animal models. In conclusion, the SSRI treatment of Fragile X patients improves mood and language; in parallel, studies on animal models suggest that compounds selectively acting on distinct 5-HT receptor subtypes might provide a targeted correction of other Fragile X phenotypes, and thus should be further tested in clinical trials for future therapy. Full article
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14 pages, 2294 KiB  
Review
Beyond the Synapse: FMR1 and FMRP Molecular Mechanisms in the Nucleus
by Nicole Hansen, Anna Dischler and Caroline Dias
Int. J. Mol. Sci. 2025, 26(1), 214; https://doi.org/10.3390/ijms26010214 - 30 Dec 2024
Viewed by 1249
Abstract
FMR1 (Fragile X messenger ribonucleoprotein 1), located on the X-chromosome, encodes the multi-functional FMR1 protein (FMRP), critical to brain development and function. Trinucleotide CGG repeat expansions at this locus cause a range of neurological disorders, collectively referred to as Fragile X-related conditions. The [...] Read more.
FMR1 (Fragile X messenger ribonucleoprotein 1), located on the X-chromosome, encodes the multi-functional FMR1 protein (FMRP), critical to brain development and function. Trinucleotide CGG repeat expansions at this locus cause a range of neurological disorders, collectively referred to as Fragile X-related conditions. The most well-known of these is Fragile X syndrome, a neurodevelopmental disorder associated with syndromic facial features, autism, intellectual disabilities, and seizures. However, CGG expansions of different sizes also confer a risk of neuropsychiatric and neurodegenerative disorders throughout the lifespan, through distinct molecular mechanisms. Although Fragile X syndrome is associated with downstream synaptic deficits and neuronal hyperexcitability, work in the past decade has demonstrated that both the causative FMR1 trinucleotide repeat expansion and FMRP itself play important roles in nuclear function and regulation, including non-canonical nucleic acid structure formation and chromatin dynamics. These effects are critical to cellular pathophysiology, although the full extent of their contribution to clinical phenotypes is only just emerging. Here, we present a focused review on some of the nuclear consequences of FMR1/FMRP dysregulation, including parallels in other repeat expansion disorders, ranging from studies in model systems to human cells and tissues. Full article
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Other

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17 pages, 2175 KiB  
Case Report
Neurobehavioral Outcomes Relate to Activation Ratio in Female Carriers of Fragile X Syndrome Full Mutation: Two Pediatric Case Studies
by Elisa Di Giorgio, Silvia Benavides-Varela, Annamaria Porru, Sara Caviola, Marco Lunghi, Paola Rigo, Giovanna Mioni, Giulia Calignano, Martina Annunziata, Eloisa Valenza, Valentina Liani, Federica Beghetti, Fabiola Spolaor, Elisa Bettella, Roberta Polli, Zimi Sawacha and Alessandra Murgia
Int. J. Mol. Sci. 2025, 26(2), 771; https://doi.org/10.3390/ijms26020771 - 17 Jan 2025
Viewed by 927
Abstract
Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder that causes a range of developmental problems including cognitive and behavioral impairment and learning disabilities. FXS is caused by full mutations (FM) of the FMR1 gene expansions to over 200 repeats, with hypermethylation of [...] Read more.
Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder that causes a range of developmental problems including cognitive and behavioral impairment and learning disabilities. FXS is caused by full mutations (FM) of the FMR1 gene expansions to over 200 repeats, with hypermethylation of the cytosine–guanine–guanine (CGG) tandem repeated region in its promoter, resulting in transcriptional silencing and loss of gene function. Female carriers of FM are typically less impaired than males. The Activation Ratio (AR), the fraction of the normal allele carried on the active X chromosome, is thought to play a crucial modifying role in defining phenotype severity. Here, we compare the cognitive, neuropsychological, adaptive, and behavioral profile of two FXS girls (10 and 11 years old) with seemingly identical FMR1 genotypic profile of FM but distinctive AR levels (70% vs. 30%). A multi-method protocol, combining molecular pathophysiology and phenotypical measures, parent reports, lab-based tasks, gait analyses, and eye-tracking was employed. Results showed that lower AR corresponds to worse performances in most (cognitive, neuropsychological, adaptive, behavioral, social, mathematical skills), but not all the considered areas (i.e., time perception and gait analysis). These observations underscore the importance of AR as a phenotypic modifying parameter in females affected with FXS. Full article
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