Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7HNYF4)

• DOT Name: E3 ubiquitin-protein ligase RNF13 (RNF13)
• Synonyms: EC 2.3.2.27; RING finger protein 13
• Gene Name: RNF13
• Related Disease:
  Developmental and epileptic encephalopathy, 73
  Myocardial infarction
  Prader-Willi syndrome
  Intellectual disability
  Sensorineural hearing loss disorder
  Coronary heart disease
• UniProt ID: RNF13_HUMAN
• PDB ID: 5ZBU; 5ZC4
• EC Number: 2.3.2.27
• Pfam ID: PF02225 ; PF13639
• Sequence:
  MLLSIGMLMLSATQVYTILTVQLFAFLNLLPVEADILAYNFENASQTFDDLPARFGYRLP
  AEGLKGFLINSKPENACEPIVPPPVKDNSSGTFIVLIRRLDCNFDIKVLNAQRAGYKAAI
  VHNVDSDDLISMGSNDIEVLKKIDIPSVFIGESSANSLKDEFTYEKGGHLILVPEFSLPL
  EYYLIPFLIIVGICLILIVIFMITKFVQDRHRARRNRLRKDQLKKLPVHKFKKGDEYDVC
  AICLDEYEDGDKLRILPCSHAYHCKCVDPWLTKTKKTCPVCKQKVVPSQGDSDSDTDSSQ
  EENEVTEHTPLLRPLASVSAQSFGALSESRSHQNMTESSDYEEDDNEDTDSSDAENEINE
  HDVVVQLQPNGERDYNIANTV
• Function: E3 ubiquitin-protein ligase that regulates cell proliferation. Involved in apoptosis regulation. Mediates ER stress-induced activation of JNK signaling pathway and apoptosis by promoting ERN1 activation and splicing of XBP1 mRNA. Also involved in protein trafficking and localization.
• Tissue Specificity: Widely expressed (at protein level). In normal pancreas, expressed in islets, but not in ducts, nor in acini (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 73	DISSRKHE	Strong	Autosomal dominant	[1]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[2]
Prader-Willi syndrome	DISYWMLU	Strong	Biomarker	[3]
Intellectual disability	DISMBNXP	moderate	Biomarker	[1]
Sensorineural hearing loss disorder	DISJV45Z	moderate	Biomarker	[1]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[2]

10 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 E3 ubiquitin-protein ligase RNF13 (RNF13).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase RNF13 (RNF13).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase RNF13 (RNF13).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RNF13 (RNF13).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase RNF13 (RNF13).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of E3 ubiquitin-protein ligase RNF13 (RNF13).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of E3 ubiquitin-protein ligase RNF13 (RNF13).	[10]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of E3 ubiquitin-protein ligase RNF13 (RNF13).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase RNF13 (RNF13).	[12]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of E3 ubiquitin-protein ligase RNF13 (RNF13).	[13]

References

• [1] Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly, Epileptic Encephalopathy, Blindness, and Failure to Thrive. Am J Hum Genet. 2019 Jan 3;104(1):179-185. doi: 10.1016/j.ajhg.2018.11.018. Epub 2018 Dec 27.
• [2] A genome-wide association study reveals susceptibility loci for myocardial infarction/coronary artery disease in Saudi Arabs.Atherosclerosis. 2016 Feb;245:62-70. doi: 10.1016/j.atherosclerosis.2015.11.019. Epub 2015 Nov 22.
• [3] A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader-Willi syndrome critical region.Hum Mol Genet. 1999 May;8(5):783-93. doi: 10.1093/hmg/8.5.783.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [10] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [11] Toxicoproteomics reveals an effect of clozapine on autophagy in human liver spheroids. Toxicol Mech Methods. 2023 Jun;33(5):401-410. doi: 10.1080/15376516.2022.2156005. Epub 2022 Dec 19.
• [12] 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.
• [13] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.