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FLASH GENE
Symbol FMR1 contributors: shn/ - updated : 26-09-2018
HGNC name fragile X mental retardation 1
HGNC id 3775
DNA
TYPE functioning gene
SPECIAL FEATURE arranged in tandem, head to head
STRUCTURE 39.18 kb     17 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Promoter
Binding site   transcription factor
motif repetitive sequence   triplet
text structure
  • a 5'utr polymorphic CGG repeat < 60, and a distinct DNA-methylation boundary at a site between 650 and 800 nucleotides upstream of the CGG repeat in the first exon
  • six evolutionarly conserved transcription factor binding sites (SP1 and SP3, MAX, USF1, NRF1, CREB and Ap2) activating the promoter
  • three sites (USF1, USF2, NRF1) maybe important for transcriptional activity in neuronally activated cell lines
  • RNA binding sites, FBS and FMRP binding sites
  • a promoter homolog to HNRPA2B1 promoter, alternatively spliced
  • methylation of lysine 4 residue on the N-tail of histone H3 (H3-K4), in the promoter and exon1
  • demethylated lysine 9 on histone H3 (H3-K9) in promoter and exon1
  • promoter is at the center of a large ( approximately 50 kb) domain of reduced intersegment interactions
  • controlled by nuclear respiratory factor 2 and the CREB family of transcription factors (NRF-1 and NRF-2 act additively while NRF-2 synergizes with CREB/ATF at FMR1 promoter)
  • . a G-quartet motif that can act as a control element of its alternative splicing in a negative autoregulatory loop
    MAPPING cloned Y linked   status confirmed
    Map cen - DXS8045 - DXS998 - FMR1 - DXS1215 - DXS8091 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    16 splicing 4140 - 537 were the only isoforms that localized to the nucleus 2015 25847585
  • also called ISO6
  • containing a novel C-terminal domain
  • 15 splicing 4077 - 516 were the only isoforms that localized to the nucleus 2015 25847585
  • also called ISO12
  • containing a novel C-terminal domain
  • 17 splicing 4411 74 632 . highest levels were observed in neurons, not localize to the nucleus . not the most abundant isoform observed in the peripheral blood cells, and brain and testis tissues 2015 25847585
  • also called ISO1
  • 16 splicing 4348 - 611 . not localized to the nucleus . in the testis, ISO7 was the predominant isoform 2015 25847585
  • also called ISO7
  • lacking exon 12, with ISO7 were the dominant splicing products
  • 16 splicing 4273 70 586 highest levels were observed in neurons 2015 25847585
    ISO9
    - splicing - - - . dominant isoform in heart, spleen, liver, kidney and fetal cerebral cortex tissues . 40p100 of all spliced isoforms in human fetal brain neuron 2015 25847585
  • containing the first splicing acceptor site in exon 17
  • - splicing - - - dominant in human adult cerebral cortex tissue, in contrast with that of human fetal cerebral cortex tissue 2015 25847585
  • lacking exon 12 and containing the second splicing acceptor site in exon 15
  • - splicing - - 439 - 2015 25847585
  • ISO21
  • skipping exon 14, with the first splicing acceptor site in exon 15 and the second splicing acceptor site in selected exon 17, may encode a truncated polypeptide
  • - splicing - - 428 - 2015 25847585
  • skipping exon 12, may encode a truncated polypeptide
  • - splicing - - 544 - 2015 25847585
  • skipping exons 11 and 12, with the second splicing acceptor site of selected exon 17, may encode a truncated polypeptide
  • - splicing - - 566 - 2015 25847585
  • with the novel splicing acceptor site of exon 15 and the selected third downstream site
  • - splicing - - 418 - 2015 25847585
  • skipping exons 12 and 15, with a novel splicing donor site of exon 14 and a novel splicing acceptor site of selected exon 16, may encode a truncated polypeptide
  • - splicing - - - in the brain, ISO17 was the predominant isoform (54 p100) 2015 25847585
  • lacking exon 12, with ISO7 were the dominant splicing products
  • - splicing - - - is a novel spliced product that was detected in testis 2015 25847585
  • exhibited exon 11 skipping, which was also detected in ISO23
  • EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Hearing/Equilibriumearinnercochlea   Homo sapiens
    Nervousbrainforebraincerebral cortex highly Homo sapiens
     brainlimbic systemhippocampus highly Homo sapiens
     brainhindbraincerebellum highly Homo sapiens
     braindiencephalonamygdala highly Homo sapiens
    Reproductivefemale systemovary    Homo sapiensFetal
     male systemtestis  highly Homo sapiens
    Visualeyeretina  moderately Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectiveadipose   
    Nervousperipherous   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Hearing / Equilibriumcochlea cell Homo sapiens
    Nervousneuron Homo sapiens
    Reproductivegerm cell Homo sapiensFetal
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal, pregnancy
    Text brain, testis, placenta, glia in synaptic development oligodendroglia progenitor cells
    PROTEIN
    PHYSICAL PROPERTIES globular
    STRUCTURE
    motifs/domains
  • N terminal IRES domain (internal ribosome entry site) binding strongly and specifically to BCYRN1, and integral tandem Agenet (Tudor) and KH motif in the N-terminal domain
  • a domain, NDF, comprising the first 134 amino acids with two copies of a newly identified Agenet motif, for protein-protein and protein-RNA interactions and with a previously unidentified dimerization site
  • two RNA binding K homology (KH1 and KH2), to associate with polyribosomal mRNPs
  • a nuclear localization signal (NLS)
  • a nuclear export signal (NES), in exon 14
  • a RGG domain, that may play a non-redundant role in the pathophysiology of the disease , RGG domain recognition by a combination of G-quadruplex and surrounding RNA sequences that have implications for the recognition of other genomic G-rich RNAs (PMID;
  • evolutionarily conserved nuclear export function associated with the endogenous C-terminus
  • mono polymer homomer , heteromer , dimer
    isoforms Precursor
    HOMOLOGY
    interspecies ortholog to fmr1, danio renio
    ortholog to Fmr1, Rattus norvegicus
    ortholog to Fmr1, Mus musculus
    ortholog to FMR1, Pan troglodytes
    intraspecies paralog to FXR1,FXR2
    Homologene
    FAMILY
  • FMR1 family
  • protein family with functional similarities such as RNA binding, polyribosomal association, and nucleocytoplasmic shuttling
  • CATEGORY RNA associated , transport carrier
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic,granule
    intracellular,cytoplasm,cytosolic,ribosome
    intracellular,nucleus,nucleoplasm,nuclear bodies
    intracellular,nuclear envelope,pore
    text
  • association with polyribosomes in the cytoplasm
  • localized in neuronal cell bodies and in neurites (in granules of neurites), dendrites and synaptososmes, distributed within granules that extended into developing axons and growth cones
  • associated with translating polyribosomes in neuronal cells
  • potential strong nucleocytoplasmic translocation, most likely in a complex with nucleolin and possibly ribosomes, in order to regulate translation of its target mRNAs
  • presence in Cajal bodies suggesting additional functions in nuclear post-transcriptional RNA metabolism
  • present predominantly in the cytoplasm, where it regulates translation of proteins that are important for synaptic function
  • basic FUNCTION
  • nucleocytoplasmic shuttling protein, regulator of gene expression at the post transcriptional level (negative regulator of translation)
  • repressing MAP1B during active synaptogenesis in neonatal brain development and HBS1L
  • repressing the translation of target mRNA at synapses
  • required for GRM1-dependent translation of DLG4 and provide insights into the pathophysiology of fragile X syndrome
  • may be participating in regulating translation of its bound mRNAs in oligodendroglia during early brain development
  • playing a role in synaptic maturation and function and required for neurotransmitter-activated protein translation at synapses
  • may be regulating trafficking of repressed mRNA complexes and influencing local protein synthesis in synapses
  • may regulate translation by acting on RNA-RNA interactions and thus on the structural status of mRNAs
  • playing a direct role in BCYRN1/mRNA annealing
  • having a role in controlling DLG4 expression
  • function as a negative regulator of the glutamate receptor (GRM) signaling pathway, which normally regulates the local protein synthesis that is crucial for GRM-long-term depression and, perhaps, activity-dependent internalization of AMPARs, necessary to learning and memory
  • acting also as a molecular adaptor between RNA granules and the neurospecific kinesin KIF3C that powers their transport along neuronal microtubules
  • having local functions in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses
  • required for the presence of behavioral circadian rhythms and this role may be relevant to the behavioral alterations observed in fragile X patients
  • may regulate neuronal translation via microRNAs and links microRNAs with human disease
  • induces synapse loss through acute postsynaptic translational regulation (FMR1 interaction with RNA and translating polyribosomes leads to synapse loss)
  • FMRP may have a role in modulation of actin dynamics, which is a key process in morphogenesis of dendritic spines
  • mouse Fmr1 had a role in rapid, activity-regulated transport of mRNAs important for synaptogenesis and neuronal plasticity
  • with FXR2, required for the presence of behavioral circadian rhythms and this role may be relevant to the behavioral alterations observed in fragile X patients
  • involved in dopamine (DA) modulation of synaptic potentiation, and key messenger for DA modulation in the forebrain
  • regulates the protein expression of several components critical for adult neural progenitor/stem cells function, including CDK4 and GSK3B
  • having potential function in adult neurogenesis
  • plays important roles in regulating the differentiation and proliferation of adult neural progenitor/stem cells
  • acting as a potent activator of KCNT1
  • regulates dendritic protein synthesis and is essential for increases in synaptic strength and in regulating homeostatic synaptic plasticity induced by retinoic acid (
  • suppresses the transition from radial glial cells (RGCs) to intermediate progenitor cells (IPCs) during neocortical development by an actin-dependent mechanism
  • constitutive FMR1 in hippocampal cells acts as a brake on group I mGluR-mediated translation and epileptogenesis
  • required for programmed cell death and clearance of developmentally-transient peptidergic neurons
  • appears to associate with the coding sequence of transcripts on which some of the ribosomes may be stalled
  • represses translation on polyribosomes in a large complex consisting of target mRNAs and stalled ribosomes
  • FMR1 and SHANK2 are central regulators of synaptic organization and function and genetic defects of these genes have effects on spine morphology and synaptic function
  • distinct roles for MEF2A, PCDH10 and FMR1 in regulated degradation of DLG4 and synapse elimination, suggesting a common deficit in activity-dependent synapse elimination among different genetic causes of autism
  • is an RNA-binding protein that controls the translation or turnover of a subset of mRNAs
  • is an RNA-binding protein that is involved in the translational regulation of several neuronal mRNAs
  • inhibits likely translation by blocking the essential components of the translational machinery from binding to the ribosome
  • nuclear FMR1 regulates genomic stability at the chromatin interface and may impact gametogenesis and some developmental aspects of fragile X syndrome
  • regulates multipolar to bipolar transition affecting neuronal migration and cortical circuitry
  • is an RNA-binding protein important for the control of translation and synaptic function
  • is likely to participate in retinal physiology, since its expression changes with light exposure
  • is a regulator of synaptic vesicle dynamics, which supports the role of FMR1 in presynaptic functions
  • is a multifunctional RNA-binding protein with crucial roles in neuronal development and function
  • plays likely a role regulating mRNAs during pivotal maturational processes in fetal germ cells, and ovarian dysfunction resulting from FMR1 premutation may have its origins during these stages of oocyte development
  • reduces presynaptic neuropeptide stores without affecting activity-independent delivery and release
  • CELLULAR PROCESS protein, translation regulation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • homodimerizing and heterodimerizing with FXR1, FXR2 (see symbols)
  • complexing with CYFIP1
  • TARDBP is physically associated with FMR1 and Staufen (STAU1) to form a functional complex, and depletion of TARDBP/FMR1/STAU1 sensitizes cells to apoptosis and DNA damages
  • INTERACTION
    DNA
    RNA
  • binds mRNAs in the nucleus
  • small molecule
    protein
  • fragile X mental retardation, autosomal homolog 1, FXR1 and fragile X mental retardation, autosomal homolog 2, FXR2 (
  • nuclear FMRP interacting protein, NUFIP (
  • Y box-binding protein 1, YB1 (
  • ubiquitin-conjugating 9, UBC9 (
  • with RANBP9(functional role of RanBP9 binding is modulation of the RNA-binding properties of FMR1)
  • associated with BCYRN1 to regulates the translation of specific mRNA at synapses
  • with MBP (target for FMR1 during oligodendrocyte development)
  • post-translationally methylated, primarily on its arginine-glycine-glycine box, by HRMT1L2, for modifying FMR1 function (suggesting that methylation occurs to limit or modulate RNA binding by FMR1)
  • interaction between FMR1/CYFIP1 and EIF4E is increased and possibly stabilized by the presence of target mRNAs
  • FMR1–TDRD3 interaction (mutation impairing this interaction might contribute to the pathogenesis of Fragile X syndrome)
  • cytoplasmic FMR1 interacting protein 1, CYFIP1 and cytoplasmic FMR1 interacting protein 2, CYFIP2 (
  • 82-kD FMRP Interacting Protein, 82-FIP (
  • multi-domain Ran-binding protein in the microtubule-organising centre, RanBPM (
  • molecular link between GRM1 and FMR1 in the anterior cingulate cortex (ACC), a key region involved in high brain cognitive and executive functions
  • interacting with MAP1B (MAP1B RNA forms an intramolecular G quadruplex structure, which is bound with high affinity and specificity by the FMR1 RGG box)
  • binds intramolecular G-quadruplex and kissing complex RNA (kcRNA) ligands via the RGG box and KH2 domain
  • interacting with SHANK1 (represses translation of SHANK1 transcripts in neurons via an interaction with its 3 prime UTR, but translation block is abolished upon the activation of GRMs and deregulated postsynaptic synthesis of SHANK1 may significantly contribute to the aberrant dendritic spine morphology caused by the absence of FMR1)
  • binds to the C terminus of KCNT1 sodium-activated potassium channel to activate the channel
  • interaction of KCNT1 channels with FMR1 serves to regulate the proposed functions of FMR1 in mRNA trafficking and translation
  • targets ERK1 and the MTOR inhibitors PTEN, NF1, and TSC2, proteins closely linked to autism, supporting the possibility that pharmacologic agents acting on the MTOR and ERK pathways may be clinically relevant for FRAXA and autism
  • FMR1 regulates translation of NOS1 in the developing human neocortex, and alterations in FMR1 posttranscriptional regulation of NOS1 in developing neocortical circuits may contribute to cognitive dysfunction in FRAXA
  • TARDBP is physically associated with fragile X mental retardation protein (FMR1) and Staufen (STAU1) to form a functional complex
  • TARDBP/FMR1/STAU1 specifically binds to the 3prime-UTR of SIRT1 mRNA (
  • MEF2A and FMR1 cooperatively regulate the expression of PCDH10
  • protein-protein interaction of RALY with EIF4A3, FMR1, and HNRNPC
  • CTCF has a complex role in regulating FMR1 expression, probably through the organization of chromatin loops between sense/antisense transcriptional regulatory regions
  • PKP4 is an important and novel FMR1 target, strongly suggesting that impaired actin cytoskeletal functions mediated by an excess of PKP4 are key aspects underlying the fragile X syndrome
  • MYO5A and kinesin play likely key roles in the assembly and subsequent transport of FMR1 granules along microtubules to the periphery of the cell
  • STUB1 ubiquitinated FMR1 for proteasomal degradation in a molecular chaperone-independent manner
  • FMR1 associates with the RNA helicase MOV10, also associated with the microRNA pathway, in an RNA-dependent manner and facilitates MOV10 association with RNAs in brain and cells, suggesting a cooperative interaction
  • MKNK1, MKNK2 increased the binding of EIF4E to the cytoplasmic FMR1-interacting protein 1 (CYFIP1), which binds the fragile-X mental retardation protein, FMR1, a translational repressor
  • potential role for GABBR1 in FMR1 regulation and potential interest of GABAB receptor signaling in FRAXA improvement
  • FMR1 and FXR2 additively promote the maturation of new neurons by regulating a common target, the AMPA receptor GRIA1, but via distinct mechanisms
  • coordinated regulation of DLG4 mRNA by FMR1 and FXR2 that ultimately affects its fine-tuning during synaptic activity.
  • functional/physical partnership between FMR1 and TARDBP that mechanistically links several neurodevelopmental disorders and neurodegenerative diseases
  • FMR1 regulation of muscle stem cells (MuSCs) activity occurs in part by the capacity of FMR1 to directly bind MYF5 transcripts and impact rates of MYF5 deadenylation
  • FMR1 interacts with the 3'UTR of the NRGN mRNA and is required for activity-dependent translation of NRGN in the synaptic compartment and contextual memory formation
  • FMR1 regulates the stability of its m6A-marked mRNA targets through YTHDF2, which could potentially contribute to the molecular pathogenesis of Fragile X syndrome (FXS)
  • DDX3X and specific initiation factors modulate FMR1 repeat-associated non-AUG-initiated translation
  • cell & other
  • associates with ribosomes during initiation and, more importantly, methylation regulates this process by influencing the ratio of FMR1-homodimer-containing mRNPs to FMR1-FXR1-heterodimer-containing mRNPs
  • REGULATION
    activated by nuclear respiratory factor 1 and transcription factor SP1
    the transcription factor AP2-alpha
    Other regulated by TFAP2A (associates with the FMR1 promoter and selectively regulates FMR1 transcription during embryonic development)
    methylation regulates the intracellular protein-protein and protein-RNA interactions of FMR1
    phosphorylated at a highly conserved serine at position 499
    ASSOCIATED DISORDERS
    corresponding disease(s) FRAXA , FXTAS , FXPOF
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional        
    reduced FMRP negatively correlated with repeat number
    constitutional       loss of function
    leads to reduced Wnt signaling, which could be responsible for altered aNPC differentiation
    tumoral     --over  
    is associated with metastasis of breast cancer
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    mental retardationfragile X 
    defective adult neurogenesis may contribute to the learning impairment and these learning deficits can be rectified by delayed restoration of FMR1 specifically in neural stem and progenitor cells
    ANIMAL & CELL MODELS
  • In neurons from Fmr1 KO mice mRNAs were deficient in glutamatergic signaling-induced dendritic localization and single mRNA particle dynamics in live neurons revealed diminished kinesis
  • Mouse KO brain showed reduced kinesin-associated mRNAs
  • Fmrp-null mice show reduced adult hippocampal neurogenesis
  • Fmr1-/- mice showed elevated response thresholds to both click and tone stimuli
  • dysregulation of Fmrp-Grm5 signaling pathway, accompanied with a downregulation of Gabrb3 expression, may contribute to the 'autistic-like' features observed in En2 mice
  • Fmr1 KO mice have decreased proinflammatory cytokine hippocampal mRNA expression, specifically interleukin (Il6 and tumor necrosis factor (Tnf), compared with wild-type mice