scholarly journals Fragile X mental retardation protein is a size-dependent translational activator

2018 ◽  
Author(s):  
Ethan J. Greenblatt ◽  
Allan C. Spradling
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X ◽  
Ovarian Follicle ◽  
Autism Spectrum ◽  
Ribosome Profiling ◽  
Large Proteins ◽  
Fragile X Mental Retardation ◽  
Stored Mrna ◽  
Neural Dysfunction

SummaryFMR1 enhances translation of large neural/oocyte proteinsMutations in the highly conserved Fragile X mental retardation gene (Fmr1) cause the most common inherited human intellectual disability/autism spectrum disorder. Fmr1 is also needed for ovarian follicle development, and lesions are the largest genetic cause of premature ovarian failure (POF). FMR1 associates with ribosomes and is thought to repress translation, but identifying functional targets has been difficult. We analyzed FMR1’s role in quiescent Drosophila oocytes stored prior to ovulation, cells that depend entirely on translation of stored mRNA. Ribosome profiling revealed that in quiescent oocytes FMR1 stimulates the translation of large proteins, including at least twelve proteins whose human homologs are associated with dominant intellectual disability disorders, and 25 others associated with neural dysfunction. Knockdown of Fmr1 in unstored oocytes did not affect embryo development, but more than 50% of embryos derived from stored oocytes lacking FMR1 developed severe neural defects. Fmr1’s previously unappreciated role promoting the translation of large proteins from stored mRNAs in oocytes and neurons may underlie POF as well as multiple aspects of neural dysfunction.

scholarly journals Fragile X mental retardation 1 gene enhances the translation of large autism-related proteins

Science ◽  
2018 ◽  
Vol 361 (6403) ◽  
pp. 709-712 ◽  
Author(s):  
Ethan J. Greenblatt ◽  
Allan C. Spradling
Keyword(s):  
Mental Retardation ◽  
Messenger Rna ◽  
Fragile X ◽  
Mrna Translation ◽  
Autism Spectrum ◽  
Ribosome Profiling ◽  
Large Proteins ◽  
Fragile X Mental Retardation ◽  
Stored Mrna ◽  
Related Proteins

Mutations in the fragile X mental retardation 1 gene (FMR1) cause the most common inherited human autism spectrum disorder. FMR1 influences messenger RNA (mRNA) translation, but identifying functional targets has been difficult. We analyzed quiescent Drosophila oocytes, which, like neural synapses, depend heavily on translating stored mRNA. Ribosome profiling revealed that FMR1 enhances rather than represses the translation of mRNAs that overlap previously identified FMR1 targets, and acts preferentially on large proteins. Human homologs of at least 20 targets are associated with dominant intellectual disability, and 30 others with recessive neurodevelopmental dysfunction. Stored oocytes lacking FMR1 usually generate embryos with severe neural defects, unlike stored wild-type oocytes, which suggests that translation of multiple large proteins by stored mRNAs is defective in fragile X syndrome and possibly other autism spectrum disorders.

scholarly journals Clinical Development of Targeted Fragile X Syndrome Treatments: An Industry Perspective

2018 ◽  
Vol 8 (12) ◽  
pp. 214 ◽  
Author(s):  
Anna Lee ◽  
Pamela Ventola ◽  
Dejan Budimirovic ◽  
Elizabeth Berry-Kravis ◽  
Jeannie Visootsak
Keyword(s):  
Clinical Trials ◽  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Basic Research ◽  
Autism Spectrum ◽  
Pharmacological Agents ◽  
Fragile X Mental Retardation ◽  
Wide Range

Fragile X syndrome (FXS) is the leading known cause of inherited intellectual disability and autism spectrum disorder. It is caused by a mutation of the fragile X mental retardation 1 (FMR1) gene, resulting in a deficit of fragile X mental retardation protein (FMRP). The clinical presentation of FXS is variable, and is typically associated with developmental delays, intellectual disability, a wide range of behavioral issues, and certain identifying physical features. Over the past 25 years, researchers have worked to understand the complex relationship between FMRP deficiency and the symptoms of FXS and, in the process, have identified several potential targeted therapeutics, some of which have been tested in clinical trials. Whereas most of the basic research to date has been led by experts at academic institutions, the pharmaceutical industry is becoming increasingly involved with not only the scientific community, but also with patient advocacy organizations, as more promising pharmacological agents are moving into the clinical stages of development. The objective of this review is to provide an industry perspective on the ongoing development of mechanism-based treatments for FXS, including identification of challenges and recommendations for future clinical trials.

scholarly journals Molecular Biomarkers in Fragile X Syndrome

2019 ◽  
Vol 9 (5) ◽  
pp. 96 ◽  
Author(s):  
Zafarullah ◽  
Tassone
Keyword(s):  
Clinical Trials ◽  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Molecular Biomarkers ◽  
Synaptic Function ◽  
Primary Role ◽  
Fragile X Mental Retardation

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability (ID) and a known monogenic cause of autism spectrum disorder (ASD). It is a trinucleotide repeat disorder, in which more than 200 CGG repeats in the 5’ untranslated region (UTR) of the fragile X mental retardation 1 (FMR1) gene causes methylation of the promoter with consequent silencing of the gene, ultimately leading to the loss of the encoded fragile X mental retardation 1 protein, FMRP. FMRP is an RNA binding protein that plays a primary role as a repressor of translation of various mRNAs, many of which are involved in the maintenance and development of neuronal synaptic function and plasticity. In addition to intellectual disability, patients with FXS face several behavioral challenges, including anxiety, hyperactivity, seizures, repetitive behavior, and problems with executive and language performance. Currently, there is no cure or approved medication for the treatment of the underlying causes of FXS, but in the past few years, our knowledge about the proteins and pathways that are dysregulated by the loss of FMRP has increased, leading to clinical trials and to the path of developing molecular biomarkers for identifying potential targets for therapies. In this paper, we review candidate molecular biomarkers that have been identified in preclinical studies in the FXS mouse animal model and are now under validation for human applications or have already made their way to clinical trials.

scholarly journals FMRP Levels in Human Peripheral Blood Leukocytes Correlates with Intellectual Disability

Diagnostics ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1780
Author(s):  
Mark Roth ◽  
Lucienne Ronco ◽  
Diego Cadavid ◽  
Blythe Durbin-Johnson ◽  
Randi J. Hagerman ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Peripheral Blood ◽  
Fragile X ◽  
Repeat Expansion ◽  
Repeat Number ◽  
Cgg Repeat ◽  
Fragile X Mental Retardation ◽  
Cgg Repeats ◽  
Fmr1 Mrna

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. FXS is an X-linked, neurodevelopmental disorder caused by a CGG trinucleotide repeat expansion in the 5′ untranslated region (UTR) of the Fragile X Mental Retardation gene, FMR1. Greater than 200 CGG repeats results in epigenetic silencing of the gene leading to the deficiency or absence of Fragile X mental retardation protein (FMRP). The loss of FMRP is considered the root cause of FXS. The relationship between neurological function and FMRP expression in peripheral blood mononuclear cells (PBMCs) has not been well established. Assays to detect and measure FMR1 and FMRP have been described; however, none are sufficiently sensitive, precise, or quantitative to properly characterize the relationships between cognitive ability and CGG repeat number, FMR1 mRNA expression, or FMRP expression measured in PBMCs. To address these limitations, two novel immunoassays were developed and optimized, an electro-chemiluminescence immunoassay and a multiparameter flow cytometry assay. Both assays were performed on PMBCs isolated from 27 study participants with FMR1 CGG repeats ranging from normal to full mutation. After correcting for methylation, a significant positive correlation between CGG repeat number and FMR1 mRNA expression levels and a significant negative correlation between FMRP levels and CGG repeat expansion was observed. Importantly, a high positive correlation was observed between intellectual quotient (IQ) and FMRP expression measured in PBMCs.

scholarly journals Comparative Behavioral Phenotypes of Fmr1 KO, Fxr2 Het, and Fmr1 KO/Fxr2 Het Mice

2019 ◽  
Vol 9 (1) ◽  
pp. 13 ◽  
Author(s):  
Rachel Saré ◽  
Christopher Figueroa ◽  
Abigail Lemons ◽  
Inna Loutaev ◽  
Carolyn Beebe Smith
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X ◽  
Protein Product ◽  
Behavioral Phenotypes ◽  
Memory Impairments ◽  
Fragile X Mental Retardation ◽  
Behavioral Abnormalities ◽  
Mental Retardation Protein ◽  
Functional Consequences

Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene leading to loss of the protein product fragile X mental retardation protein (FMRP). FXS is the most common monogenic cause of intellectual disability. There are two known mammalian paralogs of FMRP, FXR1P, and FXR2P. The functions of FXR1P and FXR2P and their possible roles in producing or modulating the phenotype observed in FXS are yet to be identified. Previous studies have revealed that mice lacking Fxr2 display similar behavioral abnormalities as Fmr1 knockout (KO) mice. In this study, we expand upon the behavioral phenotypes of Fmr1 KO and Fxr2+/− (Het) mice and compare them with Fmr1 KO/Fxr2 Het mice. We find that Fmr1 KO and Fmr1 KO/Fxr2 Het mice are similarly hyperactive compared to WT and Fxr2 Het mice. Fmr1 KO/Fxr2 Het mice have more severe learning and memory impairments than Fmr1 KO mice. Fmr1 KO mice display significantly impaired social behaviors compared to WT mice, which are paradoxically reversed in Fmr1 KO/Fxr2 Het mice. These results highlight the important functional consequences of loss or reduction of FMRP and FXR2P.

Focal areas of a high rate of fragile X in Indonesia: a long term follow up

2019 ◽  
Vol 5 (2) ◽  
pp. 67-68
Author(s):  
Sultana MH Faradz ◽  
Tri Indah Winarni
Keyword(s):  
Mental Retardation ◽  
Behavioral Problems ◽  
Fragile X ◽  
Autism Spectrum ◽  
High Rate ◽  
Learning Ability ◽  
Fragile X Mental Retardation ◽  
Cgg Repeats ◽  
Long Term Follow Up

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability (ID) and a leading cause of autism spectrum disorder (ASD). FXS is caused by an expansion of CGG repeats >200 in the 5′ untranslated region of the promotor region fragile X mental retardation 1 gene (FMR1), which is located on Xq27.3.  The abnormal CGG expansion leads to methylation and transcriptional silencing of the FMR1 gene, resulting in a reduction or loss of fragile X mental retardation 1 protein (FMRP) and causes long, thin, and immature dendritic spines, which lead to deficits in cognitive function, behavioral problems, and learning ability

scholarly journals New Targeted Treatments for Fragile X Syndrome

2019 ◽  
Vol 15 (4) ◽  
pp. 251-258 ◽  
Author(s):  
Dragana Protic ◽  
Maria J. Salcedo-Arellano ◽  
Jeanne Barbara Dy ◽  
Laura A. Potter ◽  
Randi J. Hagerman
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Behavioral Problems ◽  
Rna Binding ◽  
Fragile X ◽  
Symptomatic Treatment ◽  
Fmr1 Gene ◽  
Fragile X Mental Retardation ◽  
Cgg Repeats

Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability with prevalence rates estimated to be 1:5,000 in males and 1:8,000 in females. The increase of >200 Cytosine Guanine Guanine (CGG) repeats in the 5’ untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene results in transcriptional silencing on the FMR1 gene with a subsequent reduction or absence of fragile X mental retardation protein (FMRP), an RNA binding protein involved in the maturation and elimination of synapses. In addition to intellectual disability, common features of FXS are behavioral problems, autism, language deficits and atypical physical features. There are still no currently approved curative therapies for FXS, and clinical management continues to focus on symptomatic treatment of comorbid behaviors and psychiatric problems. Here we discuss several treatments that target the neurobiological pathway abnormal in FXS. These medications are clinically available at present and the data suggest that these medications can be helpful for those with FXS.

scholarly journals Optimization, Validation and Initial Clinical Implications of a Luminex-based Immunoassay for the Quantification of Fragile X Protein from Dried Blood Spots

2021 ◽  
Author(s):  
Anna Boggs ◽  
Lauren Schmitt ◽  
Richard McLane ◽  
Tatyana Adayev ◽  
Giuseppe LaFauci ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Clinical Relevance ◽  
Fragile X ◽  
Dried Blood Spots ◽  
Full Mutation ◽  
X Protein ◽  
Blood Spots ◽  
Fragile X Mental Retardation ◽  
Iq Scores

Abstract Background: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability affecting 1 in 4,000 males and 1 in 6-8,000 females. FXS is caused by a trinucleotide expansion in the 5’UTR of the Fragile X Mental Retardation (FMR1) gene which in full mutation carriers (>200 repeats) leads to hypermethylation and transcriptional silencing of the gene and lack of expression of Fragile X Protein (FXP, formerly known as Fragile X Mental Retardation Protein, FMRP). Phenotypic presentation of FXS is highly variable, and molecular markers explaining or predicting this variability are lacking. Recent studies suggest that trace amounts of FXP can be detected even in fully methylated individuals and may have clinical relevance; however, the lack of available reproducible, sensitive assays to detect FXP in peripheral tissue makes evaluation of peripheral FXP as a source of clinical variability challenging. Methods: We optimized a Luminex-based assay to detect FXP in dried blot spots for increased reproducibility and sensitivity by improving reagent concentrations and buffer conditions. The optimized assay was used to quantify FXP in 187 individuals (101 males, 86 females; 0-78.4 years) including 35 typically developing controls (24 males, 11 females), 103 individuals carrying full mutations (70 males, 33 females), and 49 individuals with premutations (7 males, 42 females). A subset of these individuals showed repeat number or methylation mosaicism. We investigated the clinical relevance of peripheral FXP levels by examining its relationship with general intellectual functioning in a subset of individuals with available IQ scores. Results: We show that the optimized assay is highly reproducible and detects a wide range of FXP levels. Mosaic individuals had, on average, higher FXP levels than fully methylated individuals, and trace amounts of FXP were consistently detectable in a subset of individuals with full mutation FXS. IQ scores were positively correlated with peripheral FXP levels in male and female individuals with full mutation FXS. Conclusions: We demonstrate that our optimized Luminex-based assay to detect FXP is reproducible, highly sensitive, and related to the core intellectual disability phenotype. Further, our data suggest that trace amounts of FXP detectable in dried blood spots of individuals with FXS could be clinically relevant and may be used to stratify individuals with FXS for optimized treatment. Future studies are needed with larger sample sizes, evaluating FXP across development and expanded analysis of the relevance of FXP levels for behavioral and electrophysiological phenotypes in FXS.

scholarly journals Fragile X mental retardation protein interactions with a G quadruplex structure in the 3′-untranslated region of NR2B mRNA

2015 ◽  
Vol 11 (12) ◽  
pp. 3222-3230 ◽  
Author(s):  
Snezana Stefanovic ◽  
Brett A. DeMarco ◽  
Ayana Underwood ◽  
Kathryn R. Williams ◽  
Gary J. Bassell ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Protein Interactions ◽  
Untranslated Region ◽  
Fragile X ◽  
Common Cause ◽  
Fragile X Mental Retardation ◽  
Quadruplex Structure ◽  
G Quadruplex ◽  
Mental Retardation Protein

Fragile X syndrome, the most common cause of inherited intellectual disability, is caused by a trinucleotide CGG expansion in the 5′-untranslated region of the FMR1 gene, which leads to the loss of expression of the fragile X mental retardation protein (FMRP).

scholarly journals Neuronal fragile X mental retardation protein activates glial insulin receptor mediated PDF-Tri neuron developmental clearance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dominic J. Vita ◽  
Cole J. Meier ◽  
Kendal Broadie
Keyword(s):  
Mental Retardation ◽  
Insulin Receptor ◽  
Neural Circuit ◽  
Fragile X ◽  
Receptor Activation ◽  
Autism Spectrum ◽  
Receptor Expression ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein ◽  
Insulin Receptor Signaling

AbstractGlia engulf and phagocytose neurons during neural circuit developmental remodeling. Disrupting this pruning process contributes to Fragile X syndrome (FXS), a leading cause of intellectual disability and autism spectrum disorder in mammals. Utilizing a Drosophila FXS model central brain circuit, we identify two glial classes responsible for Draper-dependent elimination of developmentally transient PDF-Tri neurons. We find that neuronal Fragile X Mental Retardation Protein (FMRP) drives insulin receptor activation in glia, promotes glial Draper engulfment receptor expression, and negatively regulates membrane-molding ESCRT-III Shrub function during PDF-Tri neuron clearance during neurodevelopment in Drosophila. In this context, we demonstrate genetic interactions between FMRP and insulin receptor signaling, FMRP and Draper, and FMRP and Shrub in PDF-Tri neuron elimination. We show that FMRP is required within neurons, not glia, for glial engulfment, indicating FMRP-dependent neuron-to-glia signaling mediates neuronal clearance. We conclude neuronal FMRP drives glial insulin receptor activation to facilitate Draper- and Shrub-dependent neuronal clearance during neurodevelopment in Drosophila.

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