FMRP expression as a potential prognostic indicator in fragile X syndrome

Tassone, Flora; Hagerman, Randi J; Iklé, David; Dyer, Pamela N.; Lampe, Megan; Willemsen, Rob; Oostra, Ben A.; Taylor, Annette K.

doi:10.1002/(sici)1096-8628(19990528)84:3<250::aid-ajmg17>3.0.co;2-4

Cited by 289 publications

(114 citation statements)

References 55 publications

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“…This is supported by studies showing a correlation of FMRP levels with intellectual function (Reiss et al, 1995;Tassone et al, 1999). (2) Our findings predict that mosaic patients may be uniquely predisposed to phenotypes that could arise from imbalanced presynaptic connectivity.…”

Section: Discussionsupporting

confidence: 76%

PresynapticFmr1Genotype Influences the Degree of Synaptic Connectivity in a Mosaic Mouse Model of Fragile X Syndrome

Hanson¹,

Madison²

2007

J. Neurosci.

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Almost all female and some male fragile X syndrome (FXS) patients are mosaic for expression of the FMR1 gene, yet all research in models of FXS has been in animals uniformly lacking Fmr1 expression. Therefore, we developed a system allowing neuronal genotype to be visualized in vitro in mouse brain slices mosaic for Fmr1 expression. Whole-cell recordings from individual pairs of presynaptic and postsynaptic neurons in organotypic hippocampal slices were used to probe the cell-autonomous effects of Fmr1 genotype in mosaic networks. These recordings revealed that wild-type presynaptic neurons formed synaptic connections at a greater rate than presynaptic neurons lacking normal Fmr1 function in mosaic networks. At the same time, the postsynaptic Fmr1 genotype did not influence the probability that a neuron received synaptic connections. Asymmetric presynaptic function during development of the brain could result in a decreased participation in network function by the portion of neurons lacking FMR1 expression.

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Section: Discussionsupporting

confidence: 76%

PresynapticFmr1Genotype Influences the Degree of Synaptic Connectivity in a Mosaic Mouse Model of Fragile X Syndrome

Hanson¹,

Madison²

2007

J. Neurosci.

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“…Furthermore, because the FMRP levels are a better predictor of disease severity than either the repeat number or methylation status [31], the TR-FRET-based FMRP assay we have described could also be useful in a clinical setting.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, compounds that increase FMRP expression might also be beneficial for such PM carriers. In addition, given that the severity of the clinical phenotype in FXS patients is inversely proportional to the FMRP levels [31], a direct and quantitative measurement of FMRP should be a better predictor of disease severity than either the number of CGG-repeats in the FMR1 gene or FMR1 mRNA levels. However, the current methods for FMRP detection such as Western blotting, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) are all limited by low sensitivity, high variability, and/or lengthy or complicated workflow.…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Screening to Identify Compounds That Increase Fragile X Mental Retardation Protein Expression in Neural Stem Cells Differentiated From Fragile X Syndrome Patient-Derived Induced Pluripotent Stem Cells

Kumari

Swaroop

Southall

et al. 2015

Stem Cells Translational Medicine

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a Key Words. Fragile X syndrome x Fragile X mental retardation protein assay x High-throughput screening x Fibroblasts x Induced pluripotent stem cells x Neural stem cells ABSTRACTFragile X syndrome (FXS), the most common form of inherited cognitive disability, is caused by a deficiency of the fragile X mental retardation protein (FMRP). In most patients, the absence of FMRP is due to an aberrant transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. FXS has no cure, and the available treatments only provide symptomatic relief. Given that FMR1 gene silencing in FXS patient cells can be partially reversed by treatment with compounds that target repressive epigenetic marks, restoring FMRP expression could be one approach for the treatment of FXS. We describe a homogeneous and highly sensitive time-resolved fluorescence resonance energy transfer assay for FMRP detection in a 1,536-well plate format. Using neural stem cells differentiated from an FXS patient-derived induced pluripotent stem cell (iPSC) line that does not express any FMRP, we screened a collection of approximately 5,000 known tool compounds and approved drugs using this FMRP assay and identified 6 compounds that modestly increase FMR1 gene expression in FXS patient cells. Although none of these compounds resulted in clinically relevant levels of FMR1 mRNA, our data provide proof of principle that this assay combined with FXS patient-derived neural stem cells can be used in a high-throughput format to identify better lead compounds for FXS drug development. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:800-808 SIGNIFICANCEIn this study, a specific and sensitive fluorescence resonance energy transfer-based assay for fragile X mental retardation protein detection was developed and optimized for high-throughput screening (HTS) of compound libraries using fragile X syndrome (FXS) patient-derived neural stem cells. The data suggest that this HTS format will be useful for the identification of better lead compounds for developing new therapeutics for FXS. This assay can also be adapted for FMRP detection in clinical and research settings.

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“…In addition, specific physical features such as long face, macrognathia, prominent ears, hyperextensible joints, flat feet, and macroorchidism in puberty are observed (Hagerman et al, 1991;Lachiewicz and Dawson, 1994;Giangreco et al, 1996). The milder phenotypes are not accounted for in the current prevalence figures (Tassone et al, 1999;Hagerman, 2006). In addition, significant phenotypic involvement has emerged in some individuals with the premutation (55-200 CGG repeats), including fragile X-associated premature ovarian insufficiency (FXPOI) in females, and fragile X-associated tremor/ataxia syndrome (FXTAS) in both male and female aging carriers Sullivan et al, 2005).…”

mentioning

confidence: 91%

Identification of Expanded Alleles of theFMR1Gene Among High-Risk Population in Indonesia by Using Blood Spot Screening

Winarni

Utari

Mundhofir

et al. 2012

Genetic Testing and Molecular Biomarkers

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The prevalence of Fragile X Syndrome (FXS) is 1 in 4000 in males and 1 in 2500 in males and females, respectively, in the general population. Several screening studies aimed at determining the prevalence of FXS have been conducted in individuals with intellectual disabilities (IDs) with a prevalence varying from 1.15% to 6.3% across different ethnic groups. A previous study in Indonesia showed an FXS prevalence of 1.9% among the ID population. A rapid, effective, and inexpensive method for FMR1 screening, using dried blood spots capable of detecting an expanded FMR1 allele in both males and females, was recently reported. We used this approach to screen 176 blood spots, collected from Central Java, Indonesia, for the presence of expanded FMR1 gene alleles. Samples were collected from high-risk populations: 112 individuals with ID, 32 obtained from individuals with diagnosis of autism spectrum disorders, and 32 individuals with a known family history of FXS. Fourteen subjects carrying an FMR1 expanded allele were identified including 7 premutations (55-200 CGG repeats) and 7 full mutations ( > 200 repeats). Of the seven subjects identified with a full mutation, one subject was from a nonfragile X family, and six from were families with a history of FXS.Introduction F ragile X syndrome (FXS), with a prevalence of 1:2500 to 1:4000 in the general population (Turner et al., 1996;Crawford et al., 2002;Hagerman, 2008), is the most common genetic cause of intellectual disability (ID) and the leading genetic cause of autism. Although prevalence estimates vary across studies, there is agreement that the risk of autism spectrum disorders (ASD) is higher in FXS than in many other neuro-developmental disorders. From recent studies, *2% to 6% of children with ASD have FXS (Li et al., 1993;Wassink et al., 2001;Estecio et al., 2002;Hagerman, 2002;Reddy, 2005), and *30% of children with FXS have ASD (see Appendix in Rogers et al., 2001;Kaufmann et al., 2004); Pervasive Developmental Disorder-Not Otherwise Specified is seen in an additional 30% (Harris et al., 2008). In fact, FXS is characterized by a broad spectrum of behavioral and emotional impairment, psychological problems, and learning disabilities in those without mental retardation or ID. In addition, specific physical features such as long face, macrognathia, prominent ears, hyperextensible joints, flat feet, and macroorchidism in puberty are observed (Hagerman et al., 1991;Lachiewicz and Dawson, 1994;Giangreco et al., 1996). The milder phenotypes are not accounted for in the current prevalence figures (Tassone et al., 1999;Hagerman, 2006). In addition, significant phenotypic involvement has emerged in some individuals with the premutation (55-200 CGG repeats), including fragile X-associated premature ovarian insufficiency (FXPOI) in females, and fragile X-associated tremor/ataxia syndrome (FXTAS) in both male and female aging carriers Sullivan et al., 2005). Prevalence for premutation alleles was *1 in 110-250 for females and 1 in 250-800 for males (Rousseau et al., 199...

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FMRP expression as a potential prognostic indicator in fragile X syndrome

Cited by 289 publications

References 55 publications

PresynapticFmr1Genotype Influences the Degree of Synaptic Connectivity in a Mosaic Mouse Model of Fragile X Syndrome

PresynapticFmr1Genotype Influences the Degree of Synaptic Connectivity in a Mosaic Mouse Model of Fragile X Syndrome

High-Throughput Screening to Identify Compounds That Increase Fragile X Mental Retardation Protein Expression in Neural Stem Cells Differentiated From Fragile X Syndrome Patient-Derived Induced Pluripotent Stem Cells

Identification of Expanded Alleles of theFMR1Gene Among High-Risk Population in Indonesia by Using Blood Spot Screening

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