Fmr1

The protein encoded by this gene binds RNA and is associated with polysomes. The encoded protein may be involved in mRNA trafficking from the nucleus to the cytoplasm. A trinucleotide repeat (CGG) in the 5' UTR is normally found at 6-53 copies, but an expansion to 55-230 repeats is the cause of fragile X syndrome. Expansion of the trinucleotide repeat may also cause one form of premature ovarian failure (POF1). Multiple alternatively spliced transcript variants that encode different protein isoforms and which are located in different cellular locations have been described for this gene. [provided by RefSeq, May 2010]

FMR1

Multifunctional polyribosome-associated RNA-binding protein that plays a central role in neuronal development and synaptic plasticity through the regulation of alternative mRNA splicing, mRNA stability, mRNA dendritic transport and postsynaptic local protein synthesis of a subset of mRNAs (PubMed:16631377, PubMed:18653529, PubMed:19166269, PubMed:23235829, PubMed:25464849).

Plays a role in the alternative splicing of its own mRNA (PubMed:18653529).

Plays a role in mRNA nuclear export (By similarity).

Together with export factor NXF2, is involved in the regulation of the NXF1 mRNA stability in neurons (By similarity).

Stabilizes the scaffolding postsynaptic density protein DLG4/PSD-95 and the myelin basic protein (MBP) mRNAs in hippocampal neurons and glial cells, respectively; this stabilization is further increased in response to metabotropic glutamate receptor (mGluR) stimulation (By similarity).

Plays a role in selective delivery of a subset of dendritic mRNAs to synaptic sites in response to mGluR activation in a kinesin-dependent manner (By similarity).

Plays a role as a repressor of mRNA translation during the transport of dendritic mRNAs to postsynaptic dendritic spines (PubMed:11532944, PubMed:11157796, PubMed:12594214, PubMed:23235829).

Component of the CYFIP1-EIF4E-FMR1 complex which blocks cap-dependent mRNA translation initiation (By similarity).

Represses mRNA translation by stalling ribosomal translocation during elongation (By similarity).

Reports are contradictory with regards to its ability to mediate translation inhibition of MBP mRNA in oligodendrocytes (PubMed:23891804).

Also involved in the recruitment of the RNA helicase MOV10 to a subset of mRNAs and hence regulates microRNA (miRNA)-mediated translational repression by AGO2 (PubMed:14703574, PubMed:17057366, PubMed:25464849).

(Microbial infection) Acts as a positive regulator of influenza A virus (IAV) replication. Required for the assembly and nuclear export of the viral ribonucleoprotein (vRNP) components.
Facilitates the assembly of miRNAs on specific target mRNAs (PubMed:17057366).

Plays also a role as an activator of mRNA translation of a subset of dendritic mRNAs at synapses (PubMed:19097999, PubMed:19166269).

In response to mGluR stimulation, FMR1-target mRNAs are rapidly derepressed, allowing for local translation at synapses (By similarity).

Binds to a large subset of dendritic mRNAs that encode a myriad of proteins involved in pre- and postsynaptic functions (PubMed:7692601, PubMed:11719189, PubMed:11157796, PubMed:12594214, PubMed:17417632, PubMed:23235829, PubMed:24448548).

Binds to 5'-ACU[GU]-3' and/or 5'-[AU]GGA-3' RNA consensus sequences within mRNA targets, mainly at coding sequence (CDS) and 3'-untranslated region (UTR) and less frequently at 5'-UTR (PubMed:23235829).

Binds to intramolecular G-quadruplex structures in the 5'- or 3'-UTRs of mRNA targets (PubMed:11719189, PubMed:18579868, PubMed:25464849, PubMed:25692235).

Binds to G-quadruplex structures in the 3'-UTR of its own mRNA (PubMed:7692601, PubMed:11532944, PubMed:12594214, PubMed:15282548, PubMed:18653529).

Binds also to RNA ligands harboring a kissing complex (kc) structure; this binding may mediate the association of FMR1 with polyribosomes (PubMed:15805463).

Binds mRNAs containing U-rich target sequences (PubMed:12927206).

Binds to a triple stem-loop RNA structure, called Sod1 stem loop interacting with FMRP (SoSLIP), in the 5'-UTR region of superoxide dismutase SOD1 mRNA (PubMed:19166269).

Binds to the dendritic, small non-coding brain cytoplasmic RNA 1 (BC1); which may increase the association of the CYFIP1-EIF4E-FMR1 complex to FMR1 target mRNAs at synapses (By similarity).

Associates with export factor NXF1 mRNA-containing ribonucleoprotein particles (mRNPs) in a NXF2-dependent manner (By similarity).

Binds to a subset of miRNAs in the brain (PubMed:14703574, PubMed:17057366).

May associate with nascent transcripts in a nuclear protein NXF1-dependent manner (PubMed:18936162).

In vitro, binds to RNA homomer; preferentially on poly(G) and to a lesser extent on poly(U), but not on poly(A) or poly(C) (PubMed:7688265, PubMed:7781595, PubMed:12950170, PubMed:15381419, PubMed:8156595).

Moreover, plays a role in the modulation of the sodium-activated potassium channel KCNT1 gating activity (PubMed:20512134).

Negatively regulates the voltage-dependent calcium channel current density in soma and presynaptic terminals of dorsal root ganglion (DRG) neurons, and hence regulates synaptic vesicle exocytosis (By similarity).

Modulates the voltage-dependent calcium channel CACNA1B expression at the plasma membrane by targeting the channels for proteosomal degradation (By similarity).

Plays a role in regulation of MAP1B-dependent microtubule dynamics during neuronal development (By similarity).

Recently, has been shown to play a translation-independent role in the modulation of presynaptic action potential (AP) duration and neurotransmitter release via large-conductance calcium-activated potassium (BK) channels in hippocampal and cortical excitatory neurons (PubMed:25561520).

Finally, FMR1 may be involved in the control of DNA damage response (DDR) mechanisms through the regulation of ATR-dependent signaling pathways such as histone H2AX/H2A.x and BRCA1 phosphorylations (PubMed:24813610).

Isoform 10:
binds to RNA homomer; preferentially on poly(G) and to a lesser extent on poly(U), but not on poly(A) or poly(C) (PubMed:24204304).

May bind to RNA in Cajal bodies (PubMed:24204304).

Isoform 6:
binds to RNA homomer; preferentially on poly(G) and to a lesser extent on poly(U), but not on poly(A) or poly(C) (PubMed:24204304).

May bind to RNA in Cajal bodies (PubMed:24204304).

Cellular response to DNA damage stimulus Source: UniProtKB
Cellular response to hydroxyurea Source: UniProtKB
Cellular response to UV Source: UniProtKB
Cellular response to virus Source: UniProtKB
Gene silencing by RNA Source: UniProtKB-KW
Glutamate receptor signaling pathway Source: UniProtKB
Modulation by host of viral RNA genome replication Source: UniProtKB
mRNA processing Source: UniProtKB-KW
mRNA transport Source: UniProtKB
Negative regulation of cytoplasmic translation Source: UniProtKB
Negative regulation of long-term synaptic depression Source: UniProtKB
Negative regulation of mRNA catabolic process Source: CAFA
Negative regulation of synaptic vesicle exocytosis Source: UniProtKB
Negative regulation of translation Source: GO_Central
Negative regulation of translational initiation Source: UniProtKB
Negative regulation of voltage-gated calcium channel activity Source: UniProtKB
Nervous system development Source: UniProtKB-KW
Positive regulation of dendritic spine development Source: UniProtKB
Positive regulation of filopodium assembly Source: UniProtKB
Positive regulation of gene silencing by miRNA Source: UniProtKB
Positive regulation of histone phosphorylation Source: UniProtKB
Positive regulation of intracellular transport of viral material Source: UniProtKB
Positive regulation of mRNA binding Source: UniProtKB
Positive regulation of proteasomal protein catabolic process Source: UniProtKB
Positive regulation of protein phosphorylation Source: GO_Central
Positive regulation of receptor internalization Source: UniProtKB
Positive regulation of response to DNA damage stimulus Source: UniProtKB
Positive regulation of translation Source: UniProtKB
Regulation of alternative mRNA splicing, via spliceosome Source: UniProtKB
Regulation of dendritic spine development Source: UniProtKB
Regulation of filopodium assembly Source: UniProtKB
Regulation of gene silencing by miRNA Source: UniProtKB
Regulation of mRNA stability Source: UniProtKB
Regulation of neuronal action potential Source: UniProtKB
Regulation of neurotransmitter secretion Source: UniProtKB
RNA splicing Source: UniProtKB-KW

Postsynaptic cell membrane; Presynaptic cell membrane; Cell membrane; Nucleus; Nucleolus; Cytoplasm; Centromere; Chromosome; Perinuclear region; Cytoplasmic ribonucleoprotein granule; Perikaryon; Neuron projection; Axon; Dendrite; Dendritic spine; Synaptosome; Growth cone; Filopodium tip; Synapse; Stress granule. Colocalizes with H2AX/H2A.x in pericentromeric heterochromatin in response to DNA damaging agents (By similarity). Localizes on meiotic pachytene-stage chromosomes (By similarity). Forms nuclear foci representing sites of ongoing DNA replication in response to DNA damaging agents (By similarity). Shuttles between nucleus and cytoplasm in a XPO1/CRM1-dependent manner (PubMed:10196376). Localizes to cytoplasmic ribonucleoprotein granules, also referred to as messenger ribonucleoprotein particles or mRNPs, along dendrites and dendritic spines (PubMed:9659908, PubMed:14532325). FMR1-containing cytoplasmic granules colocalize to F-actin-rich structures, including filopodium, spines and growth cone during the development of hippocampal neurons (By similarity). FMR1-containing cytoplasmic granules are transported out of the soma along axon and dendrite to synaptic contacts in a microtubule- and kinesin-dependent manner (PubMed:12417734, PubMed:15380484). Colocalizes with CACNA1B in the cytoplasm and at the cell membrane of neurons (By similarity). Colocalizes with CYFIP1, CYFIP2, NXF2 and ribosomes in the perinuclear region (By similarity). Colocalizes with CYFIP1 and EIF4E in dendrites and probably at synapses (By similarity). Colocalizes with FXR1, kinesin, 60S acidic ribosomal protein RPLP0 and SMN in cytoplasmic granules in the soma and neurite cell processes (PubMed:12417734, PubMed:18093976, PubMed:16636078). Colocalizes with FXR1 and FXR2 in discrete granules, called fragile X granules (FXGs), along axon and presynaptic compartments (By similarity). Colocalizes with TDRD3 in cytoplasmic stress granules (SGs) in response to various cellular stress (PubMed:18632687, PubMed:18664458, PubMed:16636078).
Isoform 6: Cytoplasm; Perinuclear region
Isoform 9: Cytoplasm
Isoform 10: Nucleus; Cajal body. Colocalizes with Colin and SMN in Cajal bodies (PubMed:24204304).
Isoform 11: Nucleus; Cajal body

Fragile X syndrome (FXS):
An X-linked dominant disease characterized by moderate to severe mental retardation, macroorchidism (enlargement of the testicles), large ears, prominent jaw, and high-pitched, jocular speech. The defect in most patients results from an amplification of a CGG repeat region in the FMR1 gene and abnormal methylation.
Fragile X tremor/ataxia syndrome (FXTAS):
In FXTAS, the expanded repeats range in size from 55 to 200 repeats and are referred to as 'premutations'. Full repeat expansions with greater than 200 repeats results in fragile X mental retardation syndrome [MIM:300624]. Carriers of the premutation typically do not show the full fragile X syndrome phenotype, but comprise a subgroup that may have some physical features of fragile X syndrome or mild cognitive and emotional problems.
Premature ovarian failure 1 (POF1):
An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol.

Phosphorylated (PubMed:14532325). Phosphorylated on several serine residues. Phosphorylation at Ser-500 is required for phosphorylation of other nearby serine residues. Phosphorylation has no effect on the binding of individual mRNA species, but may affect the association with polyribosome. Unphosphorylated FMR1 is associated with actively translating polyribosome, whereas a fraction of phosphorylated FMR1 is associated with apparently stalled polyribosome. Dephosphorylation by an activated phosphatase may release the FMR1-mediated translational repression and allow synthesis of a locally required protein at snypases (By similarity).
Monoubiquitinated. Polyubiquitinated. Ubiquitinated and targeted for proteasomal degradation after activation of metabotropic glutamate receptor (mGluR).
Monomethylated and asymmetrically dimethylated at four arginine residues of the arginine-glycine-glycine box. Methylation disrupts the binding of FMRP to RNAs through its RGG box (By similarity). Methylation is necessary for heterodimerization with FXR1, association with polyribosomes, recruitment into stress granules and translation of FMR1 target mRNAs (PubMed:16636078). Methylated by PRMT1, PRMT3 and PRMT4, in vitro (PubMed:16922515).
Isoform 10:
Undergoes proteolytic cleavage; may be specifically cleaved by calpain-1/CAPN1 in cajal bodies (PubMed:24204304).