Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWEV0T5)

• DOT Name: Fragile X messenger ribonucleoprotein 1 (FMR1)
• Synonyms: Fragile X messenger ribonucleoprotein; FMRP; Protein FMR-1
• Gene Name: FMR1
• Related Disease:
  Anxiety
  Attention deficit hyperactivity disorder
  Chromosomal disorder
  Epilepsy
  Fragile X syndrome
  Fragile X-associated tremor/ataxia syndrome
  Ovarian cancer
  Premature ovarian failure 1
  Alzheimer disease
  Anxiety disorder
  Asthma
  Autoimmune disease
  Depression
  Developmental and epileptic encephalopathy 94
  Epithelial ovarian cancer
  Hypothyroidism
  Lung neoplasm
  Mixed anxiety and depressive disorder
  Movement disorder
  Mucopolysaccharidosis II
  Multiple sclerosis
  Neoplasm
  Neurodevelopmental disorder
  Ovarian dysfunction
  Ovarian neoplasm
  Parkinsonian disorder
  Prader-Willi syndrome
  Systemic lupus erythematosus
  Trichohepatoenteric syndrome
  Tuberous sclerosis
  X-linked intellectual disability
  Dementia
  Hepatocellular carcinoma
  Neuroblastoma
  Social phobia
  Symptomatic form of fragile X syndrome in female carrier
  Breast carcinoma
  FRAXE intellectual disability
  Breast cancer
  Cerebellar ataxia
  Cognitive impairment
  Gonadal dysgenesis
  High blood pressure
  Melanoma
  Migraine disorder
  Nervous system disease
  Periventricular nodular heterotopia
  Sleep disorder
• UniProt ID: FMR1_HUMAN
• PDB ID: 2BKD; 2FMR; 2LA5; 2QND; 4OVA; 4QVZ; 4QW2; 5DE5; 5DE8; 5DEA; 5UWJ; 5UWO
• Pfam ID: PF05641 ; PF16098 ; PF12235 ; PF00013 ; PF17904 ; PF18336
• Sequence:
  MEELVVEVRGSNGAFYKAFVKDVHEDSITVAFENNWQPDRQIPFHDVRFPPPVGYNKDIN
  ESDEVEVYSRANEKEPCCWWLAKVRMIKGEFYVIEYAACDATYNEIVTIERLRSVNPNKP
  ATKDTFHKIKLDVPEDLRQMCAKEAAHKDFKKAVGAFSVTYDPENYQLVILSINEVTSKR
  AHMLIDMHFRSLRTKLSLIMRNEEASKQLESSRQLASRFHEQFIVREDLMGLAIGTHGAN
  IQQARKVPGVTAIDLDEDTCTFHIYGEDQDAVKKARSFLEFAEDVIQVPRNLVGKVIGKN
  GKLIQEIVDKSGVVRVRIEAENEKNVPQEEEIMPPNSLPSNNSRVGPNAPEEKKHLDIKE
  NSTHFSQPNSTKVQRVLVASSVVAGESQKPELKAWQGMVPFVFVGTKDSIANATVLLDYH
  LNYLKEVDQLRLERLQIDEQLRQIGASSRPPPNRTDKEKSYVTDDGQGMGRGSRPYRNRG
  HGRRGPGYTSGTNSEASNASETESDHRDELSDWSLAPTEEERESFLRRGDGRRRGGGGRG
  QGGRGRGGGFKGNDDHSRTDNRPRNPREAKGRTTDGSLQIRVDCNNERSVHTKTLQNTSS
  EGSRLRTGKDRNQKKEKPDSVDGQQPLVNGVP
• 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. Binds also 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. 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. 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 ; [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). May bind to RNA in Cajal bodies ; [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). 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.
• 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 .

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anxiety	DISIJDBA	Definitive	Genetic Variation	[1]
Attention deficit hyperactivity disorder	DISL8MX9	Definitive	Genetic Variation	[2]
Chromosomal disorder	DISM5BB5	Definitive	Biomarker	[3]
Epilepsy	DISBB28L	Definitive	Genetic Variation	[4]
Fragile X syndrome	DISE8W3A	Definitive	X-linked	[5]
Fragile X-associated tremor/ataxia syndrome	DISKB25R	Definitive	X-linked	[6]
Ovarian cancer	DISZJHAP	Definitive	Biomarker	[7]
Premature ovarian failure 1	DISYHHEN	Definitive	X-linked	[6]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[8]
Anxiety disorder	DISBI2BT	Strong	Genetic Variation	[1]
Asthma	DISW9QNS	Strong	Biomarker	[9]
Autoimmune disease	DISORMTM	Strong	Biomarker	[10]
Depression	DIS3XJ69	Strong	Genetic Variation	[1]
Developmental and epileptic encephalopathy 94	DISK16WB	Strong	Biomarker	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[12]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[13]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[14]
Mixed anxiety and depressive disorder	DISV809X	Strong	Genetic Variation	[15]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[16]
Mucopolysaccharidosis II	DIS87GLG	Strong	Genetic Variation	[17]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[18]
Neoplasm	DISZKGEW	Strong	Biomarker	[19]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[20]
Ovarian dysfunction	DIST09IB	Strong	Biomarker	[21]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[22]
Parkinsonian disorder	DISHGY45	Strong	Genetic Variation	[23]
Prader-Willi syndrome	DISYWMLU	Strong	Genetic Variation	[24]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[25]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[26]
Tuberous sclerosis	DISEMUGZ	Strong	Altered Expression	[27]
X-linked intellectual disability	DISYJBY3	Strong	Biomarker	[28]
Dementia	DISXL1WY	moderate	Genetic Variation	[29]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[30]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[31]
Social phobia	DISQGN78	moderate	Genetic Variation	[32]
Symptomatic form of fragile X syndrome in female carrier	DISJ3BV1	Supportive	X-linked	[33]
Breast carcinoma	DIS2UE88	Disputed	Biomarker	[34]
FRAXE intellectual disability	DISDPS6G	Disputed	Biomarker	[35]
Breast cancer	DIS7DPX1	Limited	Biomarker	[34]
Cerebellar ataxia	DIS9IRAV	Limited	Biomarker	[36]
Cognitive impairment	DISH2ERD	Limited	Biomarker	[37]
Gonadal dysgenesis	DISIL2ZI	Limited	Biomarker	[38]
High blood pressure	DISY2OHH	Limited	Genetic Variation	[15]
Melanoma	DIS1RRCY	Limited	Altered Expression	[34]
Migraine disorder	DISFCQTG	Limited	Genetic Variation	[13]
Nervous system disease	DISJ7GGT	Limited	Altered Expression	[39]
Periventricular nodular heterotopia	DISU3ZRI	Limited	Genetic Variation	[40]
Sleep disorder	DIS3JP1U	Limited	Genetic Variation	[13]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Sorbitol	DMAN0DE	Approved	Fragile X messenger ribonucleoprotein 1 (FMR1) increases the abundance of Sorbitol.	[51]
M3541	DMG98QO	Phase 1	Fragile X messenger ribonucleoprotein 1 (FMR1) increases the abundance of M3541.	[51]

10 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Fragile X messenger ribonucleoprotein 1 (FMR1).	[41]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Fragile X messenger ribonucleoprotein 1 (FMR1).	[42]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Fragile X messenger ribonucleoprotein 1 (FMR1).	[43]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Fragile X messenger ribonucleoprotein 1 (FMR1).	[44]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Fragile X messenger ribonucleoprotein 1 (FMR1).	[45]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Fragile X messenger ribonucleoprotein 1 (FMR1).	[46]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Fragile X messenger ribonucleoprotein 1 (FMR1).	[47]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Fragile X messenger ribonucleoprotein 1 (FMR1).	[48]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Fragile X messenger ribonucleoprotein 1 (FMR1).	[49]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Fragile X messenger ribonucleoprotein 1 (FMR1).	[50]

References

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• [12] Identification of six serum antigens and autoantibodies for the detection of early stage epithelial ovarian carcinoma by bioinformatics analysis and liquid chip analysis.Oncol Lett. 2018 Sep;16(3):3231-3240. doi: 10.3892/ol.2018.9027. Epub 2018 Jun 26.
• [13] Fragile X syndrome: An overview and update of the FMR1 gene.Clin Genet. 2018 Feb;93(2):197-205. doi: 10.1111/cge.13075. Epub 2017 Oct 1.
• [14] Instability of the CGG repeat and expression of the FMR1 protein in a male fragile X patient with a lung tumor.Am J Hum Genet. 1995 Sep;57(3):609-18.
• [15] Prevalence and risk of migraine headaches in adult fragile X premutation carriers.Clin Genet. 2013 Dec;84(6):546-51. doi: 10.1111/cge.12109. Epub 2013 Feb 21.
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• [17] Deletion Xq27.3q28 in female patient with global developmental delays and skewed X-inactivation.BMC Med Genet. 2013 May 1;14:49. doi: 10.1186/1471-2350-14-49.
• [18] A genetic study of the FMR1 gene in a Sardinian multiple sclerosis population.Neurol Sci. 2015 Dec;36(12):2213-20. doi: 10.1007/s10072-015-2339-2. Epub 2015 Jul 21.
• [19] Fragile X mental retardation protein promotes astrocytoma proliferation via the MEK/ERK signaling pathway.Oncotarget. 2016 Nov 15;7(46):75394-75406. doi: 10.18632/oncotarget.12215.
• [20] Cannabidiol (CBD) reduces anxiety-related behavior in mice via an FMRP-independent mechanism.Pharmacol Biochem Behav. 2019 Jun;181:93-100. doi: 10.1016/j.pbb.2019.05.002. Epub 2019 May 4.
• [21] Pathophysiology Mechanisms in Fragile-X Primary Ovarian Insufficiency.Methods Mol Biol. 2019;1942:165-171. doi: 10.1007/978-1-4939-9080-1_14.
• [22] Association of BRCA1/2 mutations with FMR1 genotypes: effects on menarcheal and menopausal age.Maturitas. 2013 Jun;75(2):148-51. doi: 10.1016/j.maturitas.2013.03.002. Epub 2013 Mar 23.
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• [25] A first molecular approach towards CGG repeat expansion in FMR1 gene in systemic lupus erythematosus and in Sjgren's syndrome: a preliminary report.Clin Rheumatol. 2000;19(4):262-4. doi: 10.1007/s100670070042.
• [26] Drosophila melanogaster as a Model to Study the Multiple Phenotypes, Related to Genome Stability of the Fragile-X Syndrome.Front Genet. 2019 Feb 13;10:10. doi: 10.3389/fgene.2019.00010. eCollection 2019.
• [27] Purkinje cells derived from TSC patients display hypoexcitability and synaptic deficits associated with reduced FMRP levels and reversed by rapamycin.Mol Psychiatry. 2018 Nov;23(11):2167-2183. doi: 10.1038/s41380-018-0018-4. Epub 2018 Feb 15.
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• [29] Age and CGG-repeat length are associated with neuromotor impairments in at-risk females with the FMR1 premutation.Neurobiol Aging. 2014 Sep;35(9):2179.e7-13. doi: 10.1016/j.neurobiolaging.2014.03.018. Epub 2014 Mar 20.
• [30] Circular RNAs negatively regulate cancer stem cells by physically binding FMRP against CCAR1 complex in hepatocellular carcinoma.Theranostics. 2019 May 26;9(12):3526-3540. doi: 10.7150/thno.32796. eCollection 2019.
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• [39] Mapping the landscape of tandem repeat variability by targeted long read single molecule sequencing in familial X-linked intellectual disability.BMC Med Genomics. 2018 Dec 19;11(1):123. doi: 10.1186/s12920-018-0446-7.
• [40] Periventricular heterotopia in fragile X syndrome.Neurology. 2006 Aug 22;67(4):713-5. doi: 10.1212/01.wnl.0000230223.51595.99.
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• [42] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
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• [48] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
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