FMR1

Summary

FMR1 (fragile X messenger ribonucleoprotein 1, HGNC:3775) is a protein-coding gene on chromosome Xq27.3, encoding Fragile X messenger ribonucleoprotein 1 (Q06787). 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 target…. It is haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 2332 — RefSeq curated summary.

At a glance

• Gene–disease (curated): fragile X syndrome (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 414 total — 19 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 122
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_002024

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3775
Approved symbol	FMR1
Name	fragile X messenger ribonucleoprotein 1
Location	Xq27.3
Locus type	gene with protein product
Status	Approved
Aliases	FMRP, FRAXA, MGC87458
Ensembl gene	ENSG00000102081
Ensembl biotype	protein_coding
OMIM	309550
Entrez	2332

Gene structure

Transcript identifiers

Ensembl transcripts: 47 — 34 protein_coding, 8 retained_intron, 5 nonsense_mediated_decay

ENST00000218200, ENST00000334557, ENST00000370470, ENST00000370471, ENST00000370475, ENST00000370477, ENST00000439526, ENST00000440235, ENST00000475038, ENST00000478848, ENST00000492846, ENST00000495717, ENST00000611273, ENST00000616382, ENST00000616614, ENST00000620828, ENST00000621447, ENST00000621453, ENST00000621987, ENST00000643620, ENST00000685491, ENST00000686086, ENST00000687593, ENST00000689517, ENST00000689570, ENST00000690137, ENST00000690216, ENST00000691111, ENST00000691214, ENST00000691793, ENST00000692091, ENST00000692108, ENST00000693079, ENST00000693452, ENST00000693512, ENST00000857074, ENST00000857075, ENST00000857076, ENST00000928839, ENST00000943057, ENST00000943058, ENST00000943059, ENST00000943060, ENST00000943061, ENST00000943062, ENST00000943063, ENST00000943064

RefSeq mRNA: 5 — MANE Select: NM_002024 NM_001185075, NM_001185076, NM_001185081, NM_001185082, NM_002024

CCDS: CCDS14682, CCDS55518, CCDS55519, CCDS76039

Canonical transcript exons

ENST00000370475 — 17 exons

Exon	Start	End
ENSE00000000023	147911919	147912230
ENSE00000677344	147928322	147928393
ENSE00000677360	147938099	147938161
ENSE00000677362	147940576	147940662
ENSE00000677364	147943131	147943326
ENSE00003489325	147930128	147930244
ENSE00003508085	147932425	147932595
ENSE00003554815	147936504	147936613
ENSE00003555847	147928659	147928807
ENSE00003576254	147929948	147930041
ENSE00003581550	147925540	147925633
ENSE00003632901	147937466	147937600
ENSE00003647781	147944869	147945051
ENSE00003683954	147945534	147945616
ENSE00003694421	147932685	147932763
ENSE00003749811	147921933	147921985
ENSE00003900497	147948683	147951125

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 97.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.9340 / max 387.7752, expressed in 1811 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197916	9.7739	1720
197915	8.7567	1688
197918	1.4883	884
197921	0.2763	118
209854	0.2400	91
209855	0.2002	66
197917	0.1986	67

Top tissues by expression

298 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
caput epididymis	UBERON:0004358	97.83	gold quality
corpus epididymis	UBERON:0004359	97.72	gold quality
sural nerve	UBERON:0015488	97.10	gold quality
endothelial cell	CL:0000115	96.79	gold quality
choroid plexus epithelium	UBERON:0003911	96.43	gold quality
cauda epididymis	UBERON:0004360	96.25	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.22	gold quality
colonic epithelium	UBERON:0000397	96.05	gold quality
pigmented layer of retina	UBERON:0001782	96.01	gold quality
calcaneal tendon	UBERON:0003701	95.93	gold quality
germinal epithelium of ovary	UBERON:0001304	95.82	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.49	gold quality
jejunal mucosa	UBERON:0000399	95.37	gold quality
blood vessel layer	UBERON:0004797	95.28	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.26	gold quality
superficial temporal artery	UBERON:0001614	95.25	gold quality
endometrium	UBERON:0001295	94.97	gold quality
subthalamic nucleus	UBERON:0001906	94.97	gold quality
placenta	UBERON:0001987	94.97	gold quality
substantia nigra pars compacta	UBERON:0001965	94.96	gold quality
ventricular zone	UBERON:0003053	94.77	gold quality
CA1 field of hippocampus	UBERON:0003881	94.62	gold quality
skin of hip	UBERON:0001554	94.59	gold quality
nephron tubule	UBERON:0001231	94.53	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.44	gold quality
lateral globus pallidus	UBERON:0002476	94.39	gold quality
parietal lobe	UBERON:0001872	94.35	gold quality
ovary	UBERON:0000992	94.30	gold quality
postcentral gyrus	UBERON:0002581	94.29	gold quality
oral cavity	UBERON:0000167	94.15	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
ASCL1	Repression
FGF5	Activation
FGF8	Activation
NTRK2	Activation

Upstream regulators (CollecTRI, top): CGGBP1, CREB1, CTCF, KCNIP3, MAX, MYC, NFE2L2, NFYA, NRF1, SP1, SP3, TFAP2A, USF1, USF2

miRNA regulators (miRDB)

282 targeting FMR1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-302E	99.96	70.74	2669

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Expression in lymphocytes corresponds with methylation of DNA. No association found between lymphocyte expression and IQ. (PMID:11840495)
• The loss of AGG interruptions in CGG repeats leads to greatly increased instability of the gene. (PMID:11854169)
• A single base alteration in the CGG repeat region of FMR1: possible effects on gene expression and phenotype. (PMID:11897823)
• Paternally transmitted FMR1 alleles are less stable than maternally transmitted alleles in the common and intermediate size range. (PMID:11992259)
• The timing of both X-inactivation and full mutation FMR1 allele inactivation is different, i.e. X-inactivation occurs earlier in development than inactivation of the full mutation. (PMID:12107447)
• Functional brain activation during arithmetic processing in females with fragile X Syndrome is related to FMR1 protein expression. (PMID:12112763)
• Histone modifications depict an aberrantly heterochromatinized FMR1 gene in fragile x syndrome. (PMID:12232854)
• Methylation of the arginine-glycine-rich region in this fragile X mental retardation protein differentially affects RNA binding. (PMID:12378270)
• This report is the first example of trafficking of RNA-containing granules with FMRP as a core constituent in living PC12 cells. (PMID:12417734)
• The impairment of FMR1 mRNA translation in patients with the Fragile X syndrome with FMR1 premutation is the cause of the lower FMRP levels that leads to the clinical involvement (PMID:12515381)
• The CGG repeat in the 5’UTR exhibits remarkable instability upon transmission from mothers with premutation alleles. (PMID:12529854)
• The fragile X mental retardation protein FMRP binds elongation factor 1A mRNA and negatively regulates its translation in vivo. (PMID:12594214)
• study on allelic/haplotypic fragile X associations among Indians; weak founder effect for the fragile X expansion mutation was found (PMID:12596051)
• FMRP interacts with U-rich RNAs in a yeast three-hybrid system. (PMID:12745094)
• Relationship between the molecular defect in the FMR1 gene and the clinical phenotype associated with fragile x syndrome. (PMID:12810982)
• By using cDNA-SELEX (systematic evolution of ligands by exponential enrichment), this study identified another class of human target-mRNAs which contain U rich sequences. (PMID:12927206)
• Data describe the ability of the FMRP N-terminus to form independently folded units (domains), which may play a role in its function. (PMID:12950170)
• We show that FMRP is phosphorylated between residues 483 and 521, N-terminal to the RGG box, both in murine brain and in cultured cells. (PMID:14570712)
• the most outstanding deficit, occurring especially in males with fragile X mental retardation protein, involved impaired capacity to use an intention to regulate purposeful behavior (PMID:14599277)
• FRAXA premutation strongly indicates sporadic and familial premature ovarian failure. (PMID:14746957)
• The study demonstrates that older male carriers of premutation alleles of the FMR1 gene are at high risk of developing fragil X-associated tremor/ataxia syndrome. (PMID:14747503)
• neural responses in the right ventrolateral prefrontal cortex and the left and right striatum were correlated with the level of FMR1 gene expression in fragile X syndrome (PMID:14993603)
• point mutations in the FMR1 gene may be a cause of autism and mental retardation in Japanese patients (PMID:15000256)
• Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation (PMID:15065016)
• FMRP was found to possess all the properties of a potent nucleic acid chaperone, requiring the KH motifs and RGG box for optimal activity (PMID:15096575)
• regulated by transcription factors Nrf-1 and Sp1 (PMID:15175277)
• Analysis of the methylation status of the FMR1 promoter in cells derived from patients with Fragile X syndrome. (PMID:15377638)
• CGG trinucleotide repeats of FMR1 in the premutation range affect specific neuronal circuits that are concordant with specific neuropsychological deficits; and that these deficits reflect an emerging neuropsychological phenotype of premutation FraX. (PMID:15381024)
• FMR-1 premutations is associated with males presenting with ataxia (PMID:15483640)
• histone deacetylation and H3-K9 methylation can be established and do not interfere with active gene transcription (PMID:15563507)
• FMR1 repeat size in the lower range (<80 repeats) contributes to the variation in age at menopause; thus, FMR1 could be considered a quantitative trait locus. (PMID:15608041)
• Here, we focus on one aspect of cognition that has been well documented in the fragile X full mutation, namely social cognition. (PMID:15629215)
• Single nucleotide substitutions (AGG interruptions) in the CGG tracts play an important role in the formation of the FMR1 mRNA structure. (PMID:15659577)
• experiments indicate that H3-K4 methylation and DNA demethylation are the main epigenetic switches activating the expression of the FMR1 gene, with histone acetylation playing an ancillary role (PMID:15741991)
• Extended premutation alleles are not detected are not detected in Parkinson Disease. (PMID:15742217)
• Mental retardation associated with the I304N mutation, and likely the Fragile-X syndrome more generally, may relate to a crucial role for RNAs harboring the kissing complex motif as targets for FMRP translational regulation. (PMID:15805463)
• This review of FMRP provides important insights into the regulation and functions of local protein synthesis in the neuronal periphery, and increases our understanding of how these functions can produce specific effects at individual synapses. (PMID:15861180)
• Cytoplasmic FMRP interacting protein 2 is associated with development of atopic asthma in humans. Targeting cytoplasmic FMRP interacting protein 2 could be novel strategy for treating atopic asthma. (PMID:15879417)
• AP-2alpha associates with the Fmr1 promoter in vivo and selectively regulates Fmr1 transcription during embryonic development (PMID:15930016)
• analysis of FMR1 variation in the Mexican population (PMID:15950084)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	fmr1	ENSDARG00000037433
mus_musculus	Fmr1	ENSMUSG00000000838
rattus_norvegicus	Fmr1	ENSRNOG00000057464
drosophila_melanogaster	Fmr1	FBGN0028734

Paralogs (2): FXR1 (ENSG00000114416), FXR2 (ENSG00000129245)

Protein

Protein identifiers

Fragile X messenger ribonucleoprotein 1 — Q06787 (reviewed: Q06787)

Alternative names: Fragile X messenger ribonucleoprotein, Protein FMR-1

All UniProt accessions (19): Q06787, A0A087WVL8, A0A087WWR6, A0A087WWU4, A0A087WXI3, A0A087WY29, A0A087X1M7, A0A8I5KS01, A0A8I5KT56, A0A8I5KTT6, A0A8I5KTZ9, A0A8I5KUC2, A0A8I5KWH0, A0A8I5KYA7, A0A8I5KZ21, A8MQB8, G3V0J0, Q8IXW7, X5D907

UniProt curated annotations — full annotation on UniProt →

Function. 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 target mRNAs. Acts as an mRNA regulator by mediating formation of some phase-separated membraneless compartment: undergoes liquid-liquid phase separation upon binding to target mRNAs, leading to assemble mRNAs into cytoplasmic ribonucleoprotein granules that concentrate mRNAs with associated regulatory factors. Plays a role in the alternative splicing of its own mRNA. 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. 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. Undergoes liquid-liquid phase separation following phosphorylation and interaction with CAPRIN1, promoting formation of cytoplasmic ribonucleoprotein granules that concentrate mRNAs with factors that inhibit translation and mediate deadenylation of target mRNAs. Acts as a repressor of mRNA translation in synaptic regions by mediating formation of neuronal ribonucleoprotein granules and promoting recruitmtent of EIF4EBP2. Plays a role as a repressor of mRNA translation during the transport of dendritic mRNAs to postsynaptic dendritic spines. Component of the CYFIP1-EIF4E-FMR1 complex which blocks cap-dependent mRNA translation initiation. Represses mRNA translation by stalling ribosomal translocation during elongation. Reports are contradictory with regards to its ability to mediate translation inhibition of MBP mRNA in oligodendrocytes. 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. Facilitates the assembly of miRNAs on specific target mRNAs. Also plays a role as an activator of mRNA translation of a subset of dendritic mRNAs at synapses. In response to mGluR stimulation, FMR1-target mRNAs are rapidly derepressed, allowing for local translation at synapses. Binds to a large subset of dendritic mRNAs that encode a myriad of proteins involved in pre- and postsynaptic functions. 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. Binds to intramolecular G-quadruplex structures in the 5’- or 3’-UTRs of mRNA targets. Binds to G-quadruplex structures in the 3’-UTR of its own mRNA. Also binds to RNA ligands harboring a kissing complex (kc) structure; this binding may mediate the association of FMR1 with polyribosomes. Binds mRNAs containing U-rich target sequences. 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. 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. Plays a role in mRNA nuclear export. Specifically recognizes and binds a subset of N6-methyladenosine (m6A)-containing mRNAs, promoting their nuclear export in a XPO1/CRM1-dependent manner. Together with export factor NXF2, is involved in the regulation of the NXF1 mRNA stability in neurons. Associates with export factor NXF1 mRNA-containing ribonucleoprotein particles (mRNPs) in a NXF2-dependent manner. Binds to a subset of miRNAs in the brain. May associate with nascent transcripts in a nuclear protein NXF1-dependent manner. 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). Moreover, plays a role in the modulation of the sodium-activated potassium channel KCNT1 gating activity. 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. Modulates the voltage-dependent calcium channel CACNA1B expression at the plasma membrane by targeting the channels for proteasomal degradation. Plays a role in regulation of MAP1B-dependent microtubule dynamics during neuronal development. 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. 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. Forms a cytoplasmic messenger ribonucleoprotein (mRNP) network by packaging long mRNAs, serving as a scaffold that recruits proteins and signaling molecules. This network facilitates signaling reactions by maintaining proximity between kinases and substrates. Binds to RNA homomer; preferentially on poly(G) and to a lesser extent on poly(U), but not on poly(A) or poly(C). May bind to RNA in Cajal bodies. Binds to RNA homomer; preferentially on poly(G) and to a lesser extent on poly(U), but not on poly(A) or poly(C). May bind to RNA in Cajal bodies. (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.

Subunit / interactions. Homodimer. Forms heterodimer with FXR1; heterodimerization occurs in a methylation-dependent manner. Forms heterodimer with FXR2. Homooligomer. Component of the CYFIP1-EIF4E-FMR1 complex at least composed of CYFIP, EIF4E and FMR1; this mRNA cap binding complex formation increases in presence of the brain cytoplasmic RNA BC1 and is dynamically regulated in an activity-dependent manner to repress and then possibly release dendritic mRNAs for translation in response to mGluR stimulation. Associates with the SMN core complex that contains SMN, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8 and STRAP/UNRIP. Part of a ribonucleoprotein complex with AGO2/EIF2C2 and miRNAs. Interacts with AGO2/EIF2C2. Interacts (via C-terminus) with CACNA1B; this interaction induces a decrease in the number of presynaptic functional CACNA1B channels at the cell surface. Interacts with CYFIP1; this interaction recruits CYFIP1 to capped mRNA. Interacts with CYFIP2. Interacts with EIF5; this interaction occurs in a RNA-dependent manner. Interacts with dynein. Interacts with FXR1 and FXR2. Interacts with methylated histone H3. Interacts with IGF2BP1; this interaction allows to recruit IGF2BP1 to mRNA in a FMR1-dependent manner. Interacts (via N-terminus) with KCNMB4. Interacts with KCNT1 (via C-terminus); this interaction alters gating properties of KCNT1. Interacts (via phosphorylated form) with MCRS1 (via N-terminus). Interacts with MOV10; this interaction is direct, occurs in an RNA-dependent manner on polysomes and induces association of MOV10 with RNAs. Interacts with MYO5A and PURA; these interactions occur in association with polyribosome. Interacts with NCL. Interacts with NUFIP1. Interacts (via N-terminus) with NUFIP2. Interacts with NXF1; this interaction occurs in a mRNA-dependent and polyribosome-independent manner in the nucleus. Interacts with NXF2 (via N-terminus); this interaction is direct and occurs in a NXF1 mRNA-containing mRNP complexes. Interacts with RANBP9 (via C-terminus); this interaction is direct and inhibits binding of FMR1 to RNA homomer. Interacts with RPLP0. Interacts (via C-terminus) with SMN (via C-terminus); this interaction is direct and occurs in a RNA-independent manner. Interacts with TDRD3 (via C-terminus); this interaction is direct. Interacts with YBX1; this interaction occurs in association with polyribosome. Interacts with nucleosome. Associates with polyribosome; this association occurs in a mRNA-dependent manner. Associates with cytoplasmic messenger ribonucleoprotein particles (mRNPs). Associates with microtubules in a kinesin- and dynein-dependent manner. Isoform 6 interacts (via N-terminus) with NCL (via C-terminus). Isoform 6 interacts with CYFIP2; this interaction occurs in a RNA-dependent manner. Isoform 6 interacts with EIF5; this interaction occurs in a RNA-dependent manner. Isoform 6 interacts with RPLP0. Interacts with HABP4. Interacts with SND1. Interacts (when phosphorylated by CK2) with CAPRIN1; interaction with CAPRIN1 promotes formation of a membraneless compartment. (Microbial infection) Interacts (via KH 2 domain) with influenza A nucleoprotein (NP); this interaction occurs in a RNA-dependent manner and stimulates viral ribonucleoprotein (vRNP) assembly and subsequent RNA synthesis. (Microbial infection) Interacts with Sindbis virus non-structural protein 3 (via C-terminus); this interaction inhibits the formation of host stress granules on viral mRNAs and the nsp3-FMR1 complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes.

Subcellular location. Cytoplasm. Cytoplasmic ribonucleoprotein granule. Stress granule. Perikaryon. Perinuclear region. Cell projection. Neuron projection. Axon. Dendrite. Dendritic spine. Synapse. Synaptosome. Growth cone. Filopodium tip. Postsynaptic cell membrane. Presynaptic cell membrane. Nucleus. Nucleolus. Chromosome. Centromere. Cell membrane Cytoplasm. Perinuclear region Cytoplasm Nucleus. Cajal body Nucleus. Cajal body.

Tissue specificity. Expressed in the brain, cerebellum and testis. Also expressed in epithelial tissues. Expressed in mature oligodendrocytes (OLGs). Expressed in fibroblast. Expressed in neurons, Purkinje cells and spermatogonias (at protein level). Expressed in brain, testis and placenta. Expressed in neurons and lymphocytes.

Post-translational modifications. Phosphorylated on several serine residues. Phosphorylation by casein kinase II (CK2) promotes interaction with CAPRIN1 and liquid-liquid phase separation (LLPS) for the formation of a membraneless compartment that concentrates mRNAs with associated regulatory factors. Phosphorylation at Ser-500 by CK2 promotes secondary phosphorylation of other nearby serine residues. Phosphorylation has no effect on the binding of individual mRNA species. 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 synapses. Monoubiquitinated. Polyubiquitinated. Ubiquitinated and targeted for proteasomal degradation after activation of metabotropic glutamate receptor (mGluR). Monomethylated and asymmetrically dimethylated by PRMT1, PRMT3 and PRMT4 at four arginine residues of the arginine-glycine-glycine box. Methylation decreases ability to undergo liquid-liquid phase separation (LLPS) for the formation of a membraneless compartment. Methylation does not affect mRNA-binding. Methylation is necessary for heterodimerization with FXR1, association with polyribosomes, recruitment into stress granules and translation of FMR1 target mRNAs. Undergoes proteolytic cleavage; may be specifically cleaved by calpain-1/CAPN1 in cajal bodies.

Disease relevance. Fragile X syndrome (FXS) [MIM:300624] An X-linked dominant disease characterized by moderate to severe intellectual disability, 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. The disease is caused by variants affecting the gene represented in this entry. Fragile X tremor/ataxia syndrome (FXTAS) [MIM:300623] An X-linked neurodegenerative disorder characterized by late-onset, progressive cerebellar ataxia and intention tremor followed by cognitive decline. The disease is caused by variants affecting the gene represented in this entry. Premature ovarian failure 1 (POF1) [MIM:311360] 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. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C-terminal disordered region undergoes liquid-liquid phase separation (LLPS) for the formation of a membraneless compartment that concentrates mRNAs with associated regulatory factors. The N-terminal 134 amino acids are necessary for homodimerization and RNA-binding. The N-terminal 298 amino acids are sufficient to interact with KCNMB4 and to regulate presynaptic action potential (AP) duration in neurons. The two agenet-like domains are necessary for binding to histone H3 in a methylation-dependent manner. The KH domains are necessary for mediating miRNA annealing to specific RNA targets. The KH 2 domain is necessary for binding to kissing complex (kc) RNA ligands. The RGG box domain is necessary for binding to mRNA targets that contain G-quadruplex structures. The RGG-box domain is necessary for binding to a triple stem-loop RNA structure, called Sod1 stem loop interacting with FMRP (SoSLIP), in the superoxide dismutase SOD1 mRNA. The RGG box domain is necessary for binding to its own mRNA. The RGG-box domain is necessary for binding to homomer poly(G). The C-terminal region contains a Cajal body localization signal at positions 490 through 506.

Induction. (Microbial infection) Up-regulated in response to infection by influenza A virus.

Miscellaneous. The mechanism of the severe phenotype in the Asn-304 patient lies in the sequestration of bound mRNAs in nontranslatable mRNP particles. In the absence of FMRP, these same mRNAs may be partially translated via alternate mRNPs, although perhaps abnormally localized or regulated, resulting in typical fragile X syndrome. Asn-304 mutation maps to a position within the second KH domain of FMRP that is critical for stabilizing sequence-specific RNA-protein interactions. Asn-304 mutation abrogates the association of the FMRP KH 2 domain with its target, kissing complex RNA.

Similarity. Belongs to the FMR1 family.

Isoforms (11)

UniProt ID	Names	Canonical?
Q06787-1	6	yes
Q06787-2	1
Q06787-3	2
Q06787-4	3
Q06787-5	4
Q06787-6	5
Q06787-7	7
Q06787-8	8
Q06787-9	9, B
Q06787-10	10, ISO6
Q06787-11	11, ISO12

RefSeq proteins (5): NP_001172004, NP_001172005, NP_001172010, NP_001172011, NP_002015* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004087	KH_dom	Domain
IPR004088	KH_dom_type_1	Domain
IPR008395	Agenet-like_dom	Domain
IPR022034	FMR1-like_C_core	Domain
IPR032196	FMR1_C2	Domain
IPR036612	KH_dom_type_1_sf	Homologous_superfamily
IPR040148	FMR1	Family
IPR040472	FMRP_KH0	Domain
IPR041560	Tudor_FRM1	Domain
IPR047431	Tudor_Agenet_FMR1_rpt1	Domain
IPR047436	Tudor_Agenet_FMR1_rpt2	Domain
IPR047438	KH_I_FMR1_rpt1	Domain
IPR047440	KH_I_FMR1_rpt2	Domain

Pfam: PF00013, PF05641, PF12235, PF16098, PF17904, PF18336

UniProt features (113 total): modified residue 27, strand 20, helix 19, mutagenesis site 9, compositionally biased region 8, region of interest 7, splice variant 5, sequence variant 5, domain 4, turn 4, short sequence motif 3, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
2QND	X-RAY DIFFRACTION	1.9
5UWJ	X-RAY DIFFRACTION	2.22
5UWO	X-RAY DIFFRACTION	2.35
5DEA	X-RAY DIFFRACTION	2.8
4QW2	X-RAY DIFFRACTION	2.99
4OVA	X-RAY DIFFRACTION	3
5DE5	X-RAY DIFFRACTION	3
5DE8	X-RAY DIFFRACTION	3.1
4QVZ	X-RAY DIFFRACTION	3.19
2BKD	SOLUTION NMR
2FMR	SOLUTION NMR
2LA5	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q06787-F1	69.98	0.43

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (27): 1, 337, 370, 460, 463, 471, 500, 502, 504, 511, 514, 518, 534, 534, 539, 539, 544, 544, 544, 546 …

Mutagenesis-validated functional residues (9):

Position	Phenotype
102	reduces binding to nucleosome.
103	reduces binding to nucleosome.
125–126	alters the structural integrity of the n-terminus and leads to aggregation.
500	loss of phosphorylation. does not affect interaction with mcrs1. does not affect localization to cytoplasmic granules. d
500	does not affect rna-binding to g-quadruplex structure.
527–534	reduces nucleolar localization. strongly reduces nucleolar localization; when associated with 613-e–e-617.
544	reduces arginine methylation by 80%.
546	slightly reduced methylation.
613–617	reduces nucleolar localization. strongly reduces nucleolar localization; when associated with 527-e–e-534.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 820 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GOBP_CYTOPLASMIC_TRANSLATION, GOBP_DENDRITE_DEVELOPMENT, RNGTGGGC_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_VIRUS, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_NEGATIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, PAL_PRMT5_TARGETS_UP, GOBP_REGULATION_OF_NEURONAL_SYNAPTIC_PLASTICITY, GCANCTGNY_MYOD_Q6, GOBP_ALTERNATIVE_MRNA_SPLICING_VIA_SPLICEOSOME, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN

GO Biological Process (47): regulation of alternative mRNA splicing, via spliceosome (GO:0000381), positive regulation of receptor internalization (GO:0002092), DNA repair (GO:0006281), mRNA processing (GO:0006397), mRNA export from nucleus (GO:0006406), glutamate receptor signaling pathway (GO:0007215), nervous system development (GO:0007399), RNA splicing (GO:0008380), negative regulation of translation (GO:0017148), regulatory ncRNA-mediated gene silencing (GO:0031047), stress granule assembly (GO:0034063), regulation of mRNA stability (GO:0043488), host-mediated perturbation of viral RNA genome replication (GO:0044830), positive regulation of translation (GO:0045727), negative regulation of translational initiation (GO:0045947), regulation of neurotransmitter secretion (GO:0046928), positive regulation of long-term neuronal synaptic plasticity (GO:0048170), animal organ development (GO:0048513), mRNA transport (GO:0051028), regulation of filopodium assembly (GO:0051489), positive regulation of filopodium assembly (GO:0051491), negative regulation of miRNA-mediated gene silencing (GO:0060965), regulation of dendritic spine development (GO:0060998), positive regulation of dendritic spine development (GO:0060999), cellular response to virus (GO:0098586), regulation of neuronal action potential (GO:0098908), regulation of translation at presynapse, modulating synaptic transmission (GO:0099577), membraneless organelle assembly (GO:0140694), negative regulation of long-term synaptic depression (GO:1900453), positive regulation of intracellular transport of viral material (GO:1901254), negative regulation of voltage-gated calcium channel activity (GO:1901386), positive regulation of proteasomal protein catabolic process (GO:1901800), negative regulation of synaptic vesicle exocytosis (GO:2000301), positive regulation of miRNA-mediated gene silencing (GO:2000637), negative regulation of cytoplasmic translation (GO:2000766), deadenylation-dependent decapping of nuclear-transcribed mRNA (GO:0000290), chromatin organization (GO:0006325), regulation of translation (GO:0006417), DNA damage response (GO:0006974), post-transcriptional regulation of gene expression (GO:0010608)

GO Molecular Function (31): G-quadruplex RNA binding (GO:0002151), chromatin binding (GO:0003682), RNA binding (GO:0003723), mRNA binding (GO:0003729), mRNA 3’-UTR binding (GO:0003730), microtubule binding (GO:0008017), poly(A) binding (GO:0008143), poly(U) RNA binding (GO:0008266), translation repressor activity (GO:0030371), translation initiation factor binding (GO:0031369), RNA strand annealing activity (GO:0033592), poly(G) binding (GO:0034046), siRNA binding (GO:0035197), miRNA binding (GO:0035198), signaling adaptor activity (GO:0035591), RNA stem-loop binding (GO:0035613), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), ribosome binding (GO:0043022), transmembrane transporter binding (GO:0044325), translation regulator activity (GO:0045182), protein heterodimerization activity (GO:0046982), mRNA 5’-UTR binding (GO:0048027), dynein complex binding (GO:0070840), histone H3 reader activity (GO:0140006), molecular condensate scaffold activity (GO:0140693), N6-methyladenosine-containing RNA reader activity (GO:1990247), sequence-specific mRNA binding (GO:1990825), nucleic acid binding (GO:0003676), protein binding (GO:0005515), protein-containing complex binding (GO:0044877)

GO Cellular Component (37): chromosome, centromeric region (GO:0000775), nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), chromocenter (GO:0010369), cytoplasmic stress granule (GO:0010494), postsynaptic density (GO:0014069), Cajal body (GO:0015030), membrane (GO:0016020), axon (GO:0030424), dendrite (GO:0030425), growth cone (GO:0030426), filopodium tip (GO:0032433), cytoplasmic ribonucleoprotein granule (GO:0036464), presynaptic membrane (GO:0042734), cell projection (GO:0042995), neuron projection (GO:0043005), dendritic spine (GO:0043197), perikaryon (GO:0043204), intracellular membraneless organelle (GO:0043232), axon terminus (GO:0043679), synapse (GO:0045202), postsynaptic membrane (GO:0045211), perinuclear region of cytoplasm (GO:0048471), neuronal ribonucleoprotein granule (GO:0071598), glial cell projection (GO:0097386), presynapse (GO:0098793), postsynapse (GO:0098794), dendritic filopodium (GO:1902737), growth cone filopodium (GO:1990812), ribonucleoprotein complex (GO:1990904), plasma membrane (GO:0005886), SMN complex (GO:0032797), somatodendritic compartment (GO:0036477)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
RNA binding	3
protein binding	3
intracellular membraneless organelle	3
RNA processing	2
translation	2
regulation of translation	2
negative regulation of gene expression	2
negative regulation of translation	2
poly-purine tract binding	2
regulatory RNA binding	2
nuclear lumen	2
cytoplasm	2
neuron projection	2
alternative mRNA splicing, via spliceosome	1
regulation of mRNA splicing, via spliceosome	1
regulation of receptor internalization	1
receptor internalization	1
positive regulation of receptor-mediated endocytosis	1
DNA metabolic process	1
DNA damage response	1
mRNA metabolic process	1
RNA export from nucleus	1
gene expression	1
mRNA transport	1
cell surface receptor signaling pathway	1
glutamate receptor activity	1
system development	1
negative regulation of protein metabolic process	1
membraneless organelle assembly	1
regulation of RNA stability	1
regulation of mRNA catabolic process	1
viral RNA genome replication	1
host-mediated perturbation of viral process	1
positive regulation of gene expression	1
positive regulation of protein metabolic process	1
translational initiation	1
regulation of translational initiation	1
neurotransmitter secretion	1
modulation of chemical synaptic transmission	1

Protein interactions and networks

STRING

3826 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FMR1	CYFIP1	Q7L576	998
FMR1	AGO2	Q9UKV8	993
FMR1	DICER1	Q9UPY3	988
FMR1	CYFIP2	Q96F07	987
FMR1	PURA	Q00577	985
FMR1	NUFIP2	Q7Z417	981
FMR1	AGO1	Q9UL18	971
FMR1	SND1	Q7KZF4	962
FMR1	TARDBP	Q13148	950
FMR1	AFF2	P51816	946
FMR1	NUFIP1	Q9UHK0	946
FMR1	MAP1B	P46821	941
FMR1	DLG4	P78352	938
FMR1	MECP2	P51608	912
FMR1	CPEB1	Q9BZB8	910

IntAct

421 interactions, top by confidence:

A	B	Type	Score
	EIF4E	psi-mi:“MI:0914”(association)	0.880
FMR1	FMR1	psi-mi:“MI:0407”(direct interaction)	0.690
INAVA	CYTH3	psi-mi:“MI:0914”(association)	0.640
FMR1	NUFIP2	psi-mi:“MI:0407”(direct interaction)	0.590
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
FUS	DDX3X	psi-mi:“MI:0914”(association)	0.430
FMR1	TCOF1	psi-mi:“MI:0915”(physical association)	0.400
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
DDX41	DDX39A	psi-mi:“MI:0914”(association)	0.350
HIF1AN	CNOT1	psi-mi:“MI:0914”(association)	0.350
FMR1	Kcnma1	psi-mi:“MI:0914”(association)	0.350
NBEAL2	HAX1	psi-mi:“MI:0914”(association)	0.350
Eif4e	FMR1	psi-mi:“MI:0914”(association)	0.350
DLD	NFKBIE	psi-mi:“MI:0914”(association)	0.350
DLST		psi-mi:“MI:0914”(association)	0.350
PDHA1		psi-mi:“MI:0914”(association)	0.350
DLD	IRS4	psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
DICER1	IGF2BP3	psi-mi:“MI:0914”(association)	0.350
MAPT	C11orf98	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
CAND1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
CUL2	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
SSX2IP	CCDC85C	psi-mi:“MI:2364”(proximity)	0.270
SMARCB1	KIF2A	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (479): STUB1 (Affinity Capture-Western), FMR1 (Affinity Capture-Western), FXR2 (Two-hybrid), FSD2 (Two-hybrid), FMR1 (Affinity Capture-MS), FXR1 (Affinity Capture-MS), BCL7B (Affinity Capture-MS), KBTBD2 (Affinity Capture-MS), FMR1 (Affinity Capture-MS), FMR1 (Affinity Capture-MS), NCK1 (Co-fractionation), FMR1 (Affinity Capture-MS), FMR1 (Affinity Capture-Western), FZR1 (Affinity Capture-Western), FMR1 (Proximity Label-MS)

ESM2 similar proteins: A0JM64, A0JMV4, A2VDN6, A4IFB1, A4IGK4, D3ZTQ1, O70523, O75400, P35922, P51113, P51114, P51115, P70501, P98175, Q06787, Q12872, Q15459, Q2KHP9, Q2KIA6, Q2NLB0, Q2TBT7, Q3TCX3, Q3USH5, Q5BJ56, Q5R539, Q5R9B4, Q5SFM8, Q5T8P6, Q5XI81, Q61584, Q66I22, Q6DDU9, Q6GLC9, Q6NZ18, Q6NZN0, Q7TN31, Q80TJ7, Q80WE1, Q8CGC4, Q8JZX4

Diamond homologs: F1QLR3, O70523, P35922, P51113, P51114, P51115, P51116, Q06787, Q2KHP9, Q2TBT7, Q5BJ56, Q5R9B4, Q5XI81, Q61584, Q6GLC9, Q7ZTQ5, Q80WE1, Q9NFU0, Q9WVR4, A4WWP0, A5E870, A5VTB6, A6UF34, A7HZ97, A9M9Z8, B0CK15, B2S9G0, B9JGS9, C0RG51, C3MC71, Q07V82, Q11BC3, Q1QS60, Q2YQR3, Q57A96, Q8FXS9, Q8YEB7, Q92SW0, Q13EM2, Q89WB3

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
NRF1	“up-regulates quantity by expression”	FMR1	“transcriptional regulation”
USF1	“up-regulates quantity by expression”	FMR1	“transcriptional regulation”
USF2	“up-regulates quantity by expression”	FMR1	“transcriptional regulation”
SP3	“up-regulates quantity by expression”	FMR1	“transcriptional regulation”
SP1	“up-regulates quantity by expression”	FMR1	“transcriptional regulation”
STUB1	“down-regulates quantity by destabilization”	FMR1	ubiquitination
FMR1	“up-regulates quantity”	DLG4	“post transcriptional regulation”
FMR1	“up-regulates quantity”	SHANK1	“post transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

414 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	13
Uncertain significance	100
Likely benign	29
Benign	63

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1526864	GRCh37/hg19 Xq27.3(chrX:146930611-147023367)	Pathogenic
1801490	NM_002024.6(FMR1):c.663del (p.Glu221fs)	Pathogenic
183387	NM_002024.6(FMR1):c.-129CGG[201]	Pathogenic
183388	NC_000023.9:g.146703942_146820448del	Pathogenic
2504902	NM_002024.6(FMR1):c.990+1G>T	Pathogenic
268182	NM_002024.6(FMR1):c.420-8A>G	Pathogenic
268183	NM_002024.6(FMR1):c.990+1G>A	Pathogenic
268184	NC_000023.10:g.(?147030199)(147046357_?)del	Pathogenic
29987	NM_002024.6(FMR1):c.80C>A (p.Ser27Ter)	Pathogenic
3255145	NM_002024.6(FMR1):c.1375A>T (p.Lys459Ter)	Pathogenic
3336885	NM_002024.6(FMR1):c.1411C>T (p.Arg471Ter)	Pathogenic
3359088	NM_002024.6(FMR1):c.210_211dup (p.Ala71fs)	Pathogenic
57461	GRCh38/hg38 Xq27.3(chrX:147933767-147951004)x0	Pathogenic
623467	NM_002024.6(FMR1):c.-128GGC[55_200]	Pathogenic
623468	NM_002024.6(FMR1):c.-128GGC[200_?]	Pathogenic
9969	NM_002024.6(FMR1):c.911T>A (p.Ile304Asn)	Pathogenic
9970	NM_002024.6(FMR1):c.373del (p.Thr125fs)	Pathogenic
9971	NM_002024.6(FMR1):c.52-1_52delinsTA	Pathogenic
9972	NM_002024.6:c.-128GGM[55_?]	Pathogenic
1027987	NM_002024.6(FMR1):c.1184G>A (p.Trp395Ter)	Likely pathogenic
1098346	NM_002024.6(FMR1):c.866C>T (p.Pro289Leu)	Likely pathogenic
1708227	NM_002024.6(FMR1):c.1268_1269del (p.Tyr423fs)	Likely pathogenic
1801484	NM_002024.6(FMR1):c.673G>A (p.Val225Ile)	Likely pathogenic
1801489	NM_002024.6(FMR1):c.1622_1636del (p.Gln541_Gly545del)	Likely pathogenic
2685723	GRCh37/hg19 Xq27.3(chrX:146717400-147000407)x1	Likely pathogenic
372871	NM_002024.6(FMR1):c.1256A>G (p.Tyr419Cys)	Likely pathogenic
374035	NM_002024.6(FMR1):c.199-2A>G	Likely pathogenic
3850987	NM_002024.6(FMR1):c.271-1G>A	Likely pathogenic
4293272	NM_002024.6(FMR1):c.498_500del (p.Tyr166_Gln167delinsTer)	Likely pathogenic
4813354	NM_002024.6(FMR1):c.1276-1202G>A	Likely pathogenic

SpliceAI

3045 predictions. Top by Δscore:

Variant	Effect	Δscore
X:147912196:TGG:T	donor_gain	1.0000
X:147912198:G:GT	donor_gain	1.0000
X:147912226:ACAAG:A	donor_loss	1.0000
X:147912227:CAAG:C	donor_loss	1.0000
X:147912228:AAGG:A	donor_loss	1.0000
X:147912229:AGGTA:A	donor_loss	1.0000
X:147912232:T:A	donor_loss	1.0000
X:147921929:A:AG	acceptor_gain	1.0000
X:147921929:ACAG:A	acceptor_gain	1.0000
X:147921930:C:G	acceptor_gain	1.0000
X:147921930:CAGG:C	acceptor_loss	1.0000
X:147921931:A:AG	acceptor_gain	1.0000
X:147921931:A:T	acceptor_loss	1.0000
X:147921932:G:A	acceptor_loss	1.0000
X:147921932:G:GG	acceptor_gain	1.0000
X:147921932:GGC:G	acceptor_gain	1.0000
X:147921981:AACAA:A	donor_gain	1.0000
X:147921982:ACAA:A	donor_gain	1.0000
X:147921983:CAA:C	donor_gain	1.0000
X:147921984:AA:A	donor_gain	1.0000
X:147921984:AAGTA:A	donor_loss	1.0000
X:147921985:AGTA:A	donor_loss	1.0000
X:147921986:G:GG	donor_gain	1.0000
X:147921987:TAAGT:T	donor_loss	1.0000
X:147921988:AAGT:A	donor_loss	1.0000
X:147928657:A:AG	acceptor_gain	1.0000
X:147928658:G:GA	acceptor_gain	1.0000
X:147928658:GTT:G	acceptor_gain	1.0000
X:147928658:GTTT:G	acceptor_gain	1.0000
X:147928658:GTTTT:G	acceptor_gain	1.0000

AlphaMissense

4167 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:147912198:G:A	E7K	1.000
X:147912207:G:C	G10R	1.000
X:147912216:G:C	G13R	1.000
X:147912216:G:T	G13C	1.000
X:147912217:G:A	G13D	1.000
X:147912217:G:T	G13V	1.000
X:147912220:C:A	A14D	1.000
X:147912225:T:G	Y16D	1.000
X:147921933:G:C	A18P	1.000
X:147921934:C:A	A18E	1.000
X:147921940:T:A	V20E	1.000
X:147921964:T:A	I28K	1.000
X:147921970:T:A	V30D	1.000
X:147921975:T:A	F32I	1.000
X:147921975:T:C	F32L	1.000
X:147921976:T:C	F32S	1.000
X:147921976:T:G	F32C	1.000
X:147921977:T:A	F32L	1.000
X:147921977:T:G	F32L	1.000
X:147925541:T:A	W36R	1.000
X:147925541:T:C	W36R	1.000
X:147925543:G:C	W36C	1.000
X:147925543:G:T	W36C	1.000
X:147925575:T:A	V47D	1.000
X:147925577:A:G	R48G	1.000
X:147925578:G:C	R48T	1.000
X:147925579:A:C	R48S	1.000
X:147925579:A:T	R48S	1.000
X:147925629:T:A	V65D	1.000
X:147925631:G:A	E66K	1.000

dbSNP variants (sampled 300 via entrez): RS1000048290 (X:147938271 G>T), RS1000115421 (X:147947821 G>A), RS1000387109 (X:147921074 T>G), RS1000422651 (X:147929174 T>C), RS1000581178 (X:147940859 A>G), RS1000735507 (X:147920560 G>A), RS1000871840 (X:147913696 A>G), RS1000921089 (X:147931078 T>C), RS1001281957 (X:147948531 C>G), RS1001357196 (X:147929329 A>G), RS1001366161 (X:147939077 G>C), RS1001389384 (X:147913364 C>A), RS1001439802 (X:147939423 A>G,T), RS1001502720 (X:147921231 C>T), RS1001555020 (X:147921479 A>G)

Disease associations

OMIM: gene MIM:309550 | disease phenotypes: MIM:300624, MIM:300623, MIM:311360, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
fragile X-associated tremor/ataxia syndrome	Definitive	X-linked
fragile X syndrome	Definitive	X-linked
premature ovarian failure 1	Definitive	X-linked
symptomatic form of fragile X syndrome in female carrier	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
fragile X syndrome	Definitive	XL

Mondo (7): fragile X syndrome (MONDO:0010383), fragile X-associated tremor/ataxia syndrome (MONDO:0010382), premature ovarian failure 1 (MONDO:0010706), autism (MONDO:0005260), cerebral palsy (MONDO:0006497), intellectual disability (MONDO:0001071), symptomatic form of fragile X syndrome in female carrier (MONDO:0018670)

Orphanet (5): OBSOLETE: Symptomatic form of fragile X syndrome in female carriers (Orphanet:449291), Fragile X syndrome (Orphanet:908), Fragile X-associated primary ovarian insufficiency (Orphanet:642691), Fragile X-associated tremor/ataxia syndrome (Orphanet:93256), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

122 total (30 of 122 shown, HPO-id order):

HPO	Term
HP:0000020	Urinary incontinence
HP:0000028	Cryptorchidism
HP:0000053	Macroorchidism
HP:0000135	Hypogonadism
HP:0000233	Thin vermilion border
HP:0000246	Sinusitis
HP:0000256	Macrocephaly
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000280	Coarse facial features
HP:0000298	Mask-like facies
HP:0000303	Mandibular prognathia
HP:0000365	Hearing impairment
HP:0000388	Otitis media
HP:0000389	Chronic otitis media
HP:0000400	Macrotia
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000639	Nystagmus
HP:0000713	Agitation
HP:0000716	Depression
HP:0000717	Autism
HP:0000722	Compulsive behaviors
HP:0000726	Dementia
HP:0000734	Disinhibition
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001613_16	Antineutrophil cytoplasmic antibody-associated vasculitis	2.000000e-08
GCST007233_1	Fragile X syndrome	3.000000e-10

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D002547	Cerebral Palsy	C10.228.140.140.254
D005600	Fragile X Syndrome	C10.597.606.360.455.500; C16.131.260.830.300; C16.320.180.830.300; C16.320.322.500.500; C16.320.400.525.500
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C564105	Fragile X Tremor Ataxia Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

56 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases reaction, decreases expression, affects localization, affects binding, affects reaction	3
arsenite	affects localization, affects binding, decreases reaction	2
perfluorooctane sulfonic acid	decreases expression	2
Air Pollutants	increases abundance, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
threitol	increases abundance	1
2,4,6-tribromophenol	decreases expression	1
ethylbenzene	affects cotreatment, decreases expression, increases methylation	1
bisphenol A	decreases expression	1
sodium arsenate	decreases expression	1
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid	decreases activity, decreases reaction	1
decabromobiphenyl ether	decreases expression	1
threonic acid	increases abundance	1
trichostatin A	increases expression	1
tetrahydropalmatine	decreases expression	1
aminomalonic acid	increases abundance	1
tetrabromobisphenol A	decreases expression	1
potassium chromate(VI)	decreases expression	1
nickel sulfate	decreases expression	1
ebselen	decreases activity, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
manganese(III)-tetrakis(4-benzoic acid)porphyrin	decreases activity, decreases reaction	1
K 7174	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
Bortezomib	decreases expression	1
Resveratrol	increases expression, affects cotreatment	1

Cellosaurus cell lines

92 cell lines: 45 transformed cell line, 27 embryonic stem cell, 11 induced pluripotent stem cell, 7 cancer cell line, 2 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1N27	GM04024	Finite cell line	Male
CVCL_1N28	GM04025	Transformed cell line	Male
CVCL_3659	C13589	Transformed cell line	Female
CVCL_9848	VUB11_FXS	Embryonic stem cell	Female
CVCL_9849	VUB13_FXS	Embryonic stem cell	Female
CVCL_A1MJ	ICGi026-A	Induced pluripotent stem cell	Male
CVCL_AX82	GM05847	Finite cell line	Female
CVCL_AX86	GM06852	Transformed cell line	Male
CVCL_AX87	GM06889	Transformed cell line	Female
CVCL_AX88	GM06890	Transformed cell line	Male

Clinical trials (associated diseases)

120 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00768820	PHASE4	RECRUITING	The Psychiatric and Cognitive Phenotypes in Velocardiofacial Syndrome
NCT00895752	PHASE4	COMPLETED	Riluzole in Fragile X Syndrome
NCT02642653	PHASE4	COMPLETED	Combining Lovastatin and a Parent-Implemented Language Intervention for Fragile X Syndrome
NCT05120505	PHASE4	RECRUITING	Metformin in Children With Fragile X Syndrome
NCT03816540	PHASE3	COMPLETED	Diaphragmatic Breathing and Heart Rate Variability Training for Improving Hypertension in Fragile X Associated Tremor/Ataxia
NCT01282268	PHASE3	COMPLETED	Efficacy and Safety Study of STX209 (Arbaclofen) for Social Withdrawal in Adolescents and Adults With Fragile X Syndrome
NCT01325220	PHASE3	COMPLETED	Efficacy and Safety Study of STX209 (Arbaclofen) for the Treatment of Social Withdrawal in Children With Fragile X Syndrome
NCT01555333	PHASE3	TERMINATED	An Open Label Extension Study in Subjects With Fragile X Syndrome
NCT04977986	PHASE3	COMPLETED	Clinical Study of Cannabidiol in Children, Adolescents, and Young Adults With Fragile X Syndrome
NCT05358886	PHASE3	COMPLETED	A Study of BPN14770 in Male Adults (Aged 18 to 45) With Fragile X Syndrome
NCT05367960	PHASE3	ACTIVE_NOT_RECRUITING	An Open-Label Extension Study of BPN14770 in Subjects With Fragile X Syndrome
NCT02197104	PHASE2	COMPLETED	Citocoline for Treatment in Fragile X-associated Tremor/Ataxia Syndrome
NCT02603926	PHASE2	COMPLETED	Treatment of Fragile-X Associated Tremor/Ataxia Syndrome (FXTAS) With Allopregnanolone
NCT00054730	PHASE2	COMPLETED	Effects of CX516 on Functioning in Fragile X Syndrome and Autism
NCT00420459	PHASE2	COMPLETED	A Prospective Open-label Study of Aripiprazole in Fragile X Syndrome
NCT00718341	PHASE2	COMPLETED	Efficacy, Safety and Tolerability of AFQ056 in Fragile X Patients
NCT00788073	PHASE2	COMPLETED	Safety, Tolerability and Efficacy Study of STX209 in Subjects With Fragile X Syndrome
NCT01013480	PHASE2	TERMINATED	An Open Label Extension Study of STX209 in Subjects With Fragile X Syndrome
NCT01015430	PHASE2	COMPLETED	A Study With RO4917523 in Patients With Fragile X Syndrome
NCT01120626	PHASE2	COMPLETED	Randomized Controlled Study of Donepezil in Fragile X Syndrome
NCT01253629	PHASE2	COMPLETED	Safety and Efficacy of AFQ056 in Adult Patients With Fragile X Syndrome
NCT01254045	PHASE2	COMPLETED	Double-blind Placebo Controlled Study of Oxytocin in Fragile X Syndrome
NCT01300923	PHASE2	COMPLETED	Acamprosate in Youth With Fragile X Syndrome
NCT01325740	PHASE2	SUSPENDED	A Study to Assess the Tolerability of a Single Dose of STX107 in Adults With Fragile X Syndrome
NCT01329770	PHASE2	COMPLETED	Safety and Efficacy Study of Antioxidants for the Treatment of the Fragile X Syndrome
NCT01348087	PHASE2	TERMINATED	Long-term, Safety, Tolerability and Efficacy Study of AFQ056 in Adult Patients With Fragile X Syndrome
NCT01357239	PHASE2	COMPLETED	Safety and Efficacy of AFQ056 in Adolescent Patients With Fragile X Syndrome
NCT01474746	PHASE2	COMPLETED	Trial of Sertraline to Treat Children With Fragile X Syndrome
NCT01517698	PHASE2	COMPLETED	A Study of RO4917523 in Patients With Fragile X Syndrome
NCT01725152	PHASE2	COMPLETED	Ganaxolone Treatment in Children With Fragile X Syndrome
NCT01750957	PHASE2	COMPLETED	A Study of RO4917523 in Pediatric Patients With Fragile X Syndrome
NCT01855971	PHASE2	COMPLETED	Using Epigallocatechin Gallate (EGCG) and Cognitive Training to Modulate Cognitive Performance in Patients With Fragile X Syndrome (TESFX)
NCT01894958	PHASE2	COMPLETED	A Safety Study of NNZ-2566 in Patients With Fragile X Syndrome
NCT02126995	PHASE2	COMPLETED	A 6-week, Study of MG01CI Low Dose and High Dose Compared With Placebo in Adults and Adolescents With Fragile X Syndrome
NCT02680379	PHASE2	COMPLETED	Combined Treatment of Minocycline and Lovastatin to Treat Individuals With Fragile X Syndrome
NCT02920892	PHASE2	COMPLETED	AFQ056 for Language Learning in Children With FXS
NCT03569631	PHASE2	COMPLETED	A 2-Period Crossover Study of BPN14770 in Adults Males With Fragile X Syndrome
NCT03697161	PHASE2	COMPLETED	A Study of OV101 in Individuals With Fragile X Syndrome
NCT03722290	PHASE2	COMPLETED	Metformin in Children and Adults With Fragile X Syndrome
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)