Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFPKEL7)

• DOT Name: RNA binding protein fox-1 homolog 1 (RBFOX1)
• Synonyms: Ataxin-2-binding protein 1; Fox-1 homolog A; Hexaribonucleotide-binding protein 1
• Gene Name: RBFOX1
• Related Disease:
  Childhood epilepsy with centrotemporal spikes
  Hepatitis B virus infection
  Narcolepsy
  Refractive error
  Alzheimer disease
  Anxiety
  Attention deficit hyperactivity disorder
  Cardiomyopathy
  Colorectal carcinoma
  Endometriosis
  Focal epilepsy
  Food allergy
  Glaucoma/ocular hypertension
  Hyperinsulinemia
  Major depressive disorder
  Mood disorder
  Myopia
  Neurodevelopmental disorder
  Obesity
  Peripheral arterial disease
  Pervasive developmental disorder
  Rheumatoid arthritis
  Schizophrenia
  Temporal lobe epilepsy
  Allergic rhinitis
  Epilepsy, idiopathic generalized
  Primary biliary cholangitis
  Autism spectrum disorder
  Carcinoma
  Diabetic retinopathy
  Epilepsy
  facioscapulohumeral muscular dystrophy
  Gout
  Intellectual disability
  Lung cancer
  Macular corneal dystrophy
  Myotonic dystrophy
  Myotonic dystrophy type 1
  Obsolete autism susceptibility 1
• UniProt ID: RFOX1_HUMAN
• PDB ID: 2ERR; 2N82; 4ZKA; 7VRL
• Pfam ID: PF12414 ; PF00076
• Sequence:
  MNCEREQLRGNQEAAAAPDTMAQPYASAQFAPPQNGIPAEYTAPHPHPAPEYTGQTTVPE
  HTLNLYPPAQTHSEQSPADTSAQTVSGTATQTDDAAPTDGQPQTQPSENTENKSQPKRLH
  VSNIPFRFRDPDLRQMFGQFGKILDVEIIFNERGSKGFGFVTFENSADADRAREKLHGTV
  VEGRKIEVNNATARVMTNKKTVNPYTNGWKLNPVVGAVYSPEFYAGTVLLCQANQEGSSM
  YSAPSSLVYTSAMPGFPYPAATAAAAYRGAHLRGRGRTVYNTFRAAAPPPPIPAYGGVVY
  QDGFYGADIYGGYAAYRYAQPTPATAAAYSDSYGRVYAADPYHHALAPAPTYGVGAMNAF
  APLTDAKTRSHADDVGLVLSSLQASIYRGGYNRFAPY
• Function: RNA-binding protein that regulates alternative splicing events by binding to 5'-UGCAUGU-3' elements. Regulates alternative splicing of tissue-specific exons and of differentially spliced exons during erythropoiesis.
• Tissue Specificity: Predominantly expressed in muscle and brain.
• Reactome Pathway: MECP2 regulates transcription factors (R-HSA-9022707)

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Childhood epilepsy with centrotemporal spikes	DISKT2L5	Definitive	CausalMutation	[1]
Hepatitis B virus infection	DISLQ2XY	Definitive	Genetic Variation	[2]
Narcolepsy	DISLCNLI	Definitive	Genetic Variation	[3]
Refractive error	DISWNEQ1	Definitive	Genetic Variation	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Anxiety	DISIJDBA	Strong	Genetic Variation	[6]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[7]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[9]
Endometriosis	DISX1AG8	Strong	Biomarker	[10]
Focal epilepsy	DIS4LY5L	Strong	Genetic Variation	[11]
Food allergy	DISMQ1BP	Strong	Genetic Variation	[12]
Glaucoma/ocular hypertension	DISLBXBY	Strong	Genetic Variation	[13]
Hyperinsulinemia	DISIDWT6	Strong	Altered Expression	[14]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[15]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[6]
Myopia	DISK5S60	Strong	Genetic Variation	[16]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[17]
Obesity	DIS47Y1K	Strong	Genetic Variation	[18]
Peripheral arterial disease	DIS78WFB	Strong	Genetic Variation	[19]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[17]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[20]
Schizophrenia	DISSRV2N	Strong	Biomarker	[21]
Temporal lobe epilepsy	DISNOPXX	Strong	Genetic Variation	[11]
Allergic rhinitis	DIS3U9HN	moderate	Genetic Variation	[22]
Epilepsy, idiopathic generalized	DISODZC9	moderate	Genetic Variation	[23]
Primary biliary cholangitis	DIS43E0O	Disputed	Genetic Variation	[24]
Autism spectrum disorder	DISXK8NV	Limited	Biomarker	[17]
Carcinoma	DISH9F1N	Limited	Biomarker	[25]
Diabetic retinopathy	DISHGUJM	Limited	Genetic Variation	[26]
Epilepsy	DISBB28L	Limited	Autosomal dominant	[27]
facioscapulohumeral muscular dystrophy	DISSE0H0	Limited	Altered Expression	[28]
Gout	DISHC0U7	Limited	Genetic Variation	[29]
Intellectual disability	DISMBNXP	Limited	Altered Expression	[30]
Lung cancer	DISCM4YA	Limited	Genetic Variation	[31]
Macular corneal dystrophy	DISOLD0H	Limited	Altered Expression	[32]
Myotonic dystrophy	DISNBEMX	Limited	Biomarker	[33]
Myotonic dystrophy type 1	DISJC0OX	Limited	Altered Expression	[33]
Obsolete autism susceptibility 1	DIS7NKP8	Limited	Unknown	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of RNA binding protein fox-1 homolog 1 (RBFOX1).	[35]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of RNA binding protein fox-1 homolog 1 (RBFOX1).	[36]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of RNA binding protein fox-1 homolog 1 (RBFOX1).	[37]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of RNA binding protein fox-1 homolog 1 (RBFOX1).	[38]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of RNA binding protein fox-1 homolog 1 (RBFOX1).	[39]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of RNA binding protein fox-1 homolog 1 (RBFOX1).	[41]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of RNA binding protein fox-1 homolog 1 (RBFOX1).	[39]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of RNA binding protein fox-1 homolog 1 (RBFOX1).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of RNA binding protein fox-1 homolog 1 (RBFOX1).	[42]

References

• [1] Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.Eur J Hum Genet. 2018 Feb;26(2):258-264. doi: 10.1038/s41431-017-0034-x. Epub 2018 Jan 22.
• [2] New loci associated with chronic hepatitis B virus infection in Han Chinese.Nat Genet. 2013 Dec;45(12):1499-503. doi: 10.1038/ng.2809. Epub 2013 Oct 27.
• [3] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [4] Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.Nat Genet. 2013 Mar;45(3):314-8. doi: 10.1038/ng.2554. Epub 2013 Feb 10.
• [5] Inference of RNA decay rate from transcriptional profiling highlights the regulatory programs of Alzheimer's disease.Nat Commun. 2017 Oct 13;8(1):909. doi: 10.1038/s41467-017-00867-z.
• [6] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [7] Genetic Markers of ADHD-Related Variations in Intracranial Volume.Am J Psychiatry. 2019 Mar 1;176(3):228-238. doi: 10.1176/appi.ajp.2018.18020149.
• [8] Characterization of Ca(V)1.2 exon 33 heterozygous knockout mice and negative correlation between Rbfox1 and Ca(V)1.2 exon 33 expressions in human heart failure.Channels (Austin). 2018 Jan 1;12(1):51-57. doi: 10.1080/19336950.2017.1381805.
• [9] Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion.Mol Cancer. 2013 Jan 3;12:1. doi: 10.1186/1476-4598-12-1.
• [10] Systemic oxidative stress as a possible mechanism underlying the pathogenesis of mild endometriosis-related infertility.Reprod Biomed Online. 2019 Nov;39(5):785-794. doi: 10.1016/j.rbmo.2019.06.011. Epub 2019 Jun 26.
• [11] Extending the phenotypic spectrum of RBFOX1 deletions: Sporadic focal epilepsy.Epilepsia. 2015 Sep;56(9):e129-33. doi: 10.1111/epi.13076. Epub 2015 Jul 15.
• [12] Copy Number Variations in CTNNA3 and RBFOX1 Associate with Pediatric Food Allergy.J Immunol. 2015 Aug 15;195(4):1599-607. doi: 10.4049/jimmunol.1402310. Epub 2015 Jul 17.
• [13] Genome-wide association and admixture analysis of glaucoma in the Women's Health Initiative.Hum Mol Genet. 2014 Dec 15;23(24):6634-43. doi: 10.1093/hmg/ddu364. Epub 2014 Jul 15.
• [14] Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival.J Biol Chem. 2017 Feb 24;292(8):3466-3480. doi: 10.1074/jbc.M116.748335. Epub 2017 Jan 11.
• [15] Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.Nat Neurosci. 2019 Mar;22(3):343-352. doi: 10.1038/s41593-018-0326-7. Epub 2019 Feb 4.
• [16] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [17] RBFOX1, encoding a splicing regulator, is a candidate gene for aggressive behavior.Eur Neuropsychopharmacol. 2020 Jan;30:44-55. doi: 10.1016/j.euroneuro.2017.11.012. Epub 2017 Nov 23.
• [18] Evaluation of A2BP1 as an obesity gene.Diabetes. 2010 Nov;59(11):2837-45. doi: 10.2337/db09-1604. Epub 2010 Aug 19.
• [19] Genetic Variants in the Bone Morphogenic Protein Gene Family Modify the Association between Residential Exposure to Traffic and Peripheral Arterial Disease.PLoS One. 2016 Apr 15;11(4):e0152670. doi: 10.1371/journal.pone.0152670. eCollection 2016.
• [20] Genetic influences on susceptibility to rheumatoid arthritis in African-Americans.Hum Mol Genet. 2019 Mar 1;28(5):858-874. doi: 10.1093/hmg/ddy395.
• [21] Convergent Evidence That ZNF804A Is a Regulator of Pre-messenger RNA Processing and Gene Expression.Schizophr Bull. 2019 Oct 24;45(6):1267-1278. doi: 10.1093/schbul/sby183.
• [22] Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis.BMC Med Genomics. 2014 Aug 2;7:48. doi: 10.1186/1755-8794-7-48.
• [23] Copy number variations and susceptibility to lateral temporal epilepsy: a study of 21 pedigrees.Epilepsia. 2014 Oct;55(10):1651-8. doi: 10.1111/epi.12767. Epub 2014 Sep 19.
• [24] A2BP1 as a novel susceptible gene for primary biliary cirrhosis in Japanese patients.Hum Immunol. 2010 May;71(5):520-4. doi: 10.1016/j.humimm.2010.02.009. Epub 2010 Mar 6.
• [25] High-resolution genomic analysis does not qualify atypical plexus papilloma as a separate entity among choroid plexus tumors.J Neuropathol Exp Neurol. 2015 Feb;74(2):110-20. doi: 10.1097/NEN.0000000000000154.
• [26] Genome-wide meta-analysis for severe diabetic retinopathy.Hum Mol Genet. 2011 Jun 15;20(12):2472-81. doi: 10.1093/hmg/ddr121. Epub 2011 Mar 26.
• [27] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [28] Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD).PLoS Genet. 2013;9(1):e1003186. doi: 10.1371/journal.pgen.1003186. Epub 2013 Jan 3.
• [29] Gout and type 2 diabetes have a mutual inter-dependent effect on genetic risk factors and higher incidences.Rheumatology (Oxford). 2012 Apr;51(4):715-20. doi: 10.1093/rheumatology/ker373. Epub 2011 Dec 16.
• [30] Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels.Elife. 2019 Aug 20;8:e49673. doi: 10.7554/eLife.49673.
• [31] Genome-wide analysis of survival in early-stage non-small-cell lung cancer.J Clin Oncol. 2009 Jun 1;27(16):2660-7. doi: 10.1200/JCO.2008.18.7906. Epub 2009 May 4.
• [32] Upregulation of RBFOX1 in the malformed cortex of patients with intractable epilepsy and in cultured rat neurons.Int J Mol Med. 2015 Mar;35(3):597-606. doi: 10.3892/ijmm.2015.2061. Epub 2015 Jan 5.
• [33] RBFOX1 cooperates with MBNL1 to control splicing in muscle, including events altered in myotonic dystrophy type 1.PLoS One. 2014 Sep 11;9(9):e107324. doi: 10.1371/journal.pone.0107324. eCollection 2014.
• [34] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [35] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [36] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [37] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [38] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [39] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [40] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [41] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [42] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.