FMR1 Mutant Marmosets Show Fragile X Syndrome Phenotypes
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PROVIDER: PRJNA1130839 | ENA |
REPOSITORIES: ENA
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Project description:Fragile X syndrome (FXS) is the leading monogenic cause of autism spectrum disorder and intellectual disability, caused by silencing of the FMR1 gene. To determine the effect of FMRP loss on the mRNA profile in a marmoset model of FXS, we performed RNA-sequencing of brain samples from neonatal wild-type and FMR1 mutant marmosets.
2025-07-16 | GSE271271 | GEO
Project description:Fragile X Syndrome Patient–Derived Neurons Developing in the Mouse Brain Show FMR1-Dependent Phenotypes
| PRJNA837598 | ENA
Project description:Fragile X Syndrome Patient-Derived Neurons Developing in the Mouse Brain Show FMR1-Dependent Phenotypes
| PRJNA837605 | ENA
Project description:Fragile X Syndrome Patient-Derived Neurons Developing in the Mouse Brain Show FMR1-Dependent Phenotypes
| PRJNA655137 | ENA
Project description:Fragile X syndrome (FXS) is a monogenic cause of intellectual disability, developmental delay, and autism spectrum disorder (ASD), estimated to occur in 1 in 5,000 males and 1 in 4,000 to 1 in 8,000 females. It is caused by a CGG trinucleotide repeat expansion in the 5’ untranslated region of the fragile X messenger ribonucleoprotein 1 (FMR1) gene located at Xq27.3. A full mutation, greater than 200 CGG repeats, leads to silencing of the FMR1 gene and consequent loss of its product, the fragile X messenger ribonucleoprotein (FMRP). We generated FMR1 mutant common marmosets (Callithrix jacchus) using the CRISPR/Cas9 system and performed proteomic analysis of their neonatal forebrains to identify molecular changes associated with FMR1 deficiency. We analyzed samples from two wild-type (WT) and two FMR1 mutant marmosets.
2025-07-16 | PXD066203 | JPOST Repository
Project description:ene pleiotropy defines the capacity of a gene to impact multiple phenotypic characters. The Fragile X Mental Retardation 1 (FMR1) gene is a candidate for pleiotropy, as it controls protein synthesis through its product, the translational regulator FMRP. As FMR1 loss-of-function leads to neurodevelopmental defects and Fragile X Syndrome (FXS), intellectual disability and autism, FMR1 functions have been mostly studied in the brain. FMR1-deficiency could also have yet unexplored consequences in periphery and impact metabolism through translational repression in peripheral organs. We combined 1H NMR-based metabolic phenotyping and proteomics to reveal the pleiotropic metabolic effects associated with FMR1-deficiency in mouse and human. We demonstrate that Fmr1-deficiency in the mouse increases hepatic translation, improves glucose tolerance and insulin sensitivity and reduces adiposity, while enhancing -adrenergic driven lipolysis and utilization of lipid energetic substrates. Last, we provide converging evidences in FXS patients that the levels of glucose, insulin and free fatty acids are modified, suggesting that FMR1-deficiency also drives metabolic readjustments in human. As part of a larger study investigating the involvement of fmr in metabolic alteration in fmr1-KO mice, fmr1-KO mouse livers were analysed by MS.
2022-02-28 | PXD007241 | Pride
Project description:Aberrant alternative splicing of mRNAs results in dysregulated gene expression in multiple neurological disorders. Here we show that hundreds of mRNAs are incorrectly expressed and spliced in white blood cells and brain tissue of individuals with fragile X syndrome (FXS). Surprisingly, the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene is transcribed in >70% of the FXS tissues. In all FMR1 expressing FXS tissues, FMR1 RNA itself is mis-spliced in a CGG expansion-dependent manner to generate the little-known FMR1-217 RNA isoform, which is comprised of FMR1 exon 1 and a pseudo-exon in intron 1. FMR1-217 is also expressed in FXS premutation carrier-derived skin fibroblasts and brain tissue. We show that in cells aberrantly expressing mis-spliced FMR1, antisense oligonucleotide (ASO) treatment reduces FMR1-217, rescues full-length FMR1 RNA, and restores FMRP (Fragile X Messenger RibonucleoProtein) to normal levels. Notably, FMR1 gene reactivation in transcriptionally silent FXS cells using 5-aza-2′-deoxycytidine (5-AzadC), which prevents DNA methylation, increases FMR1-217 RNA levels but not FMRP. ASO treatment of cells prior to 5-AzadC application rescues full-length FMR1 expression and restores FMRP. These findings indicate that mis-regulated RNA processing events in blood could serve as potent biomarkers for FXS and that in those individuals expressing FMR1-217, ASO treatment may offer a new therapeutic approach to mitigate the disorder.
2023-06-14 | GSE202177 | GEO
Project description:Aberrant alternative splicing of mRNAs results in dysregulated gene expression in multiple neurological disorders. Here we show that hundreds of mRNAs are incorrectly expressed and spliced in white blood cells and brain tissue of individuals with fragile X syndrome (FXS). Surprisingly, the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene is transcribed in >70% of the FXS tissues. In all FMR1 expressing FXS tissues, FMR1 RNA itself is mis-spliced in a CGG expansion-dependent manner to generate the little-known FMR1-217 RNA isoform, which is comprised of FMR1 exon 1 and a pseudo-exon in intron 1. FMR1-217 is also expressed in FXS premutation carrier-derived skin fibroblasts and brain tissue. We show that in cells aberrantly expressing mis-spliced FMR1, antisense oligonucleotide (ASO) treatment reduces FMR1-217, rescues full-length FMR1 RNA, and restores FMRP (Fragile X Messenger RibonucleoProtein) to normal levels. Notably, FMR1 gene reactivation in transcriptionally silent FXS cells using 5-aza-2′-deoxycytidine (5-AzadC), which prevents DNA methylation, increases FMR1-217 RNA levels but not FMRP. ASO treatment of cells prior to 5-AzadC application rescues full-length FMR1 expression and restores FMRP. These findings indicate that mis-regulated RNA processing events in blood could serve as potent biomarkers for FXS and that in those individuals expressing FMR1-217, ASO treatment may offer a new therapeutic approach to mitigate the disorder.
2023-06-14 | GSE202178 | GEO
Project description:Fragile X syndrome (FXS) is a common form of inherited intellectual disability and is caused by an expansion of CGG repeats located in the 5Õ untranslated region (UTR) of the FMR1 gene, leading to hypermethylation and silencing of this locus. While the dramatic increase in DNA methylation (DNAm) of the FMR1 full mutation allele is well documented, the extent that these changes affect DNAm throughout the entire gene and the rest of the genome remains unexplored. Here, we examine the genome-wide methylation in peripheral blood (N = 9) as well as induced pluripotent stem cells (iPSCs; N = 10) from FXS individuals and controls (N = 53 and 9, respectively) and find the expected significant DNAm differences in the FMR1 promoter and 5Õ UTR, but also that these changes inversely persist throughout the FMR1 gene body. Importantly, we find there are no additional differential methylated loci (DML) throughout the remainder of the genome, indicating that the aberrant methylation of the FMR1 in FXS is locus-specific and does not change DNAm genome-wide. This study provides a comprehensive methylation profile of FXS and refines mechanistic considerations of FMR1 silencing. A total of 62 blood (53 controls + 9 Fragile X) samples analyzed using a linear regression model.
2013-04-15 | E-GEOD-41273 | biostudies-arrayexpress
Project description:Fragile X syndrome (FXS) is caused primarily by a CGG repeat expansion mutation in the FMR1 gene that triggers its epigenetic silencing. In order to investigate the role of different epigenetic regulatory layers in the silencing of FMR1 expression, we tested a collection of epigenetic modulators for the ability to reactivate the FMR1 locus. While inhibitors of DNA methylatransferase induced the highest levels of FMR1 mRNA expression, a combination of a DNMT inhibitor and a novel epigenetic agent was able to potentiate the effect of reactivating treatment. To better assess the rescue effect observed following direct demethylation, we characterized the long-term and genome-wide effects of FMR1 reactivation, and established an in vivo system for FMR1 reactivating therapy analysis. Systemic treatment with a DNMT inhibitor in mice carrying transplants of differentiated FXS-iPSCs was able to robustly induce FMR1 expression in the affected tissue, which was maintained for a prolonged period of time. Finally, we show a proof-of-principle for FMR1 reactivating therapy in the context of the central nervous system.
2019-03-06 | GSE112145 | GEO