Details of Drug Off-Target (DOT)

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

• DOT Name: RNA-binding protein 20 (RBM20)
• Synonyms: RNA-binding motif protein 20
• Gene Name: RBM20
• Related Disease:
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1DD
  Cardiac failure
  Congestive heart failure
  Atrial fibrillation
  Cardiomyopathy, familial restrictive, 1
  Obsolete familial isolated dilated cardiomyopathy
  Cardiac disease
  Arrhythmia
  Cardiomyopathy
  Congenital heart disease
  Familial atrial fibrillation
  Familial dilated cardiomyopathy
  Hypertrophic cardiomyopathy
• UniProt ID: RBM20_HUMAN
• Sequence:
  MVLAAAMSQDADPSGPEQPDRVACSVPGARASPAPSGPRGMQQPPPPPQPPPPPQAGLPQ
  IIQNAAKLLDKNPFSVSNPNPLLPSPASLQLAQLQAQLTLHRLKLAQTAVTNNTAAATVL
  NQVLSKVAMSQPLFNQLRHPSVITGPHGHAGVPQHAAAIPSTRFPSNAIAFSPPSQTRGP
  GPSMNLPNQPPSAMVMHPFTGVMPQTPGQPAVILGIGKTGPAPATAGFYEYGKASSGQTY
  GPETDGQPGFLPSSASTSGSVTYEGHYSHTGQDGQAAFSKDFYGPNSQGSHVASGFPAEQ
  AGGLKSEVGPLLQGTNSQWESPHGFSGQSKPDLTAGPMWPPPHNQPYELYDPEEPTSDRT
  PPSFGGRLNNSKQGFIGAGRRAKEDQALLSVRPLQAHELNDFHGVAPLHLPHICSICDKK
  VFDLKDWELHVKGKLHAQKCLVFSENAGIRCILGSAEGTLCASPNSTAVYNPAGNEDYAS
  NLGTSYVPIPARSFTQSSPTFPLASVGTTFAQRKGAGRVVHICNLPEGSCTENDVINLGL
  PFGKVTNYILMKSTNQAFLEMAYTEAAQAMVQYYQEKSAVINGEKLLIRMSKRYKELQLK
  KPGKAVAAIIQDIHSQRERDMFREADRYGPERPRSRSPVSRSLSPRSHTPSFTSCSSSHS
  PPGPSRADWGNGRDSWEHSPYARREEERDPAPWRDNGDDKRDRMDPWAHDRKHHPRQLDK
  AELDERPEGGRPHREKYPRSGSPNLPHSVSSYKSREDGYYRKEPKAKSDKYLKQQQDAPG
  RSRRKDEARLRESRHPHPDDSGKEDGLGPKVTRAPEGAKAKQNEKNKTKRTDRDQEGADD
  RKENTMAENEAGKEEQEGMEESPQSVGRQEKEAEFSDPENTRTKKEQDWESESEAEGESW
  YPTNMEELVTVDEVGEEEDFIVEPDIPELEEIVPIDQKDKICPETCLCVTTTLDLDLAQD
  FPKEGVKAVGNGAAEISLKSPRELPSASTSCPSDMDVEMPGLNLDAERKPAESETGLSLE
  DSDCYEKEAKGVESSDVHPAPTVQQMSSPKPAEERARQPSPFVDDCKTRGTPEDGACEGS
  PLEEKASPPIETDLQNQACQEVLTPENSRYVEMKSLEVRSPEYTEVELKQPLSLPSWEPE
  DVFSELSIPLGVEFVVPRTGFYCKLCGLFYTSEETAKMSHCRSAVHYRNLQKYLSQLAEE
  GLKETEGADSPRPEDSGIVPRFERKKL
• Function: RNA-binding protein that acts as a regulator of mRNA splicing of a subset of genes encoding key structural proteins involved in cardiac development, such as TTN (Titin), CACNA1C, CAMK2D or PDLIM5/ENH. Acts as a repressor of mRNA splicing: specifically binds the 5'UCUU-3' motif that is predominantly found within intronic sequences of pre-mRNAs, leading to the exclusion of specific exons in target transcripts. RBM20-mediated exon skipping is hormone-dependent and is essential for TTN isoform transition in both cardiac and skeletal muscles. RBM20-mediated exon skipping of TTN provides substrates for the formation of circular RNA (circRNAs) from the TTN transcripts. Together with RBM24, promotes the expression of short isoforms of PDLIM5/ENH in cardiomyocytes.
• Tissue Specificity: Mainly expressed in the heart . Also expressed in skeletal muscle tissues, ovary, small intestine and colon .

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dilated cardiomyopathy	DISX608J	Definitive	Autosomal dominant	[1]
Dilated cardiomyopathy 1DD	DIS9YDCO	Definitive	Autosomal dominant	[2]
Cardiac failure	DISDC067	Strong	Biomarker	[3]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[3]
Atrial fibrillation	DIS15W6U	moderate	Genetic Variation	[4]
Cardiomyopathy, familial restrictive, 1	DIS4AJ17	moderate	Biomarker	[5]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[6]
Cardiac disease	DISVO1I5	Disputed	Biomarker	[7]
Arrhythmia	DISFF2NI	Limited	Genetic Variation	[8]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[2]
Congenital heart disease	DISQBA23	Limited	Biomarker	[9]
Familial atrial fibrillation	DISL4AGF	Limited	Biomarker	[4]
Familial dilated cardiomyopathy	DISBHDU9	Limited	Genetic Variation	[10]
Hypertrophic cardiomyopathy	DISQG2AI	Limited	Autosomal dominant	[1]

8 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 20 (RBM20).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of RNA-binding protein 20 (RBM20).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of RNA-binding protein 20 (RBM20).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of RNA-binding protein 20 (RBM20).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of RNA-binding protein 20 (RBM20).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of RNA-binding protein 20 (RBM20).	[16]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of RNA-binding protein 20 (RBM20).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of RNA-binding protein 20 (RBM20).	[16]

1 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 increases the methylation of RNA-binding protein 20 (RBM20).	[18]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy. Circ Heart Fail. 2019 Mar;12(3):e005371. doi: 10.1161/CIRCHEARTFAILURE.118.005371.
• [3] Splicing Factor RBM20 Regulates Transcriptional Network of Titin Associated and Calcium Handling Genes in The Heart.Int J Biol Sci. 2018 Mar 9;14(4):369-380. doi: 10.7150/ijbs.24117. eCollection 2018.
• [4] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [5] Molecular Characterization of Pediatric Restrictive Cardiomyopathy from Integrative Genomics.Sci Rep. 2017 Jan 18;7:39276. doi: 10.1038/srep39276.
• [6] Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy. J Am Coll Cardiol. 2009 Sep 1;54(10):930-41. doi: 10.1016/j.jacc.2009.05.038.
• [7] RNA-binding proteins RBM20 and PTBP1 regulate the alternative splicing of FHOD3.Int J Biochem Cell Biol. 2019 Jan;106:74-83. doi: 10.1016/j.biocel.2018.11.009. Epub 2018 Nov 20.
• [8] RBM20 Mutations Induce an Arrhythmogenic Dilated Cardiomyopathy Related to Disturbed Calcium Handling.Circulation. 2018 Sep 25;138(13):1330-1342. doi: 10.1161/CIRCULATIONAHA.117.031947.
• [9] Double de novo mutations in dilated cardiomyopathy with cardiac arrest.J Electrocardiol. 2019 Mar-Apr;53:40-43. doi: 10.1016/j.jelectrocard.2018.12.015. Epub 2018 Dec 21.
• [10] Phosphorylation of the RSRSP stretch is critical for splicing regulation by RNA-Binding Motif Protein 20 (RBM20) through nuclear localization.Sci Rep. 2018 Jun 12;8(1):8970. doi: 10.1038/s41598-018-26624-w.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] 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.
• [13] 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.
• [14] Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells. Toxicol Appl Pharmacol. 2017 Sep 15;331:154-163.
• [15] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] 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.