Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM52ZF5)

• DOT Name: Dendrin (DDN)
• Gene Name: DDN
• Related Disease:
  Nephropathy
  Focal segmental glomerulosclerosis
  IgA nephropathy
  Macular corneal dystrophy
  Nephrotic syndrome
  Schizophrenia
  Bipolar disorder
• UniProt ID: DEND_HUMAN
• Pfam ID: PF15498
• Sequence:
  MLDGPLFSEGPDSPRELQDEESGSCLWVQKSKLLVIEVKTISCHYSRRAPSRQPMDFQAS
  HWARGFQNRTCGPRPGSPQPPPRRPWASRVLQEATNWRAGPLAEVRAREQEKRKAASQER
  EAKETERKRRKAGGARRSPPGRPRPEPRNAPRVAQLAGLPAPLRPERLAPVGRAPRPSAQ
  PQSDPGSAWAGPWGGRRPGPPSYEAHLLLRGSAGTAPRRRWDRPPPYVAPPSYEGPHRTL
  GTKRGPGNSQVPTSSAPAATPARTDGGRTKKRLDPRIYRDVLGAWGLRQGQGLLGGSPGC
  GAARARPEPGKGVVEKSLGLAAADLNSGSDSHPQAKATGSAGTEIAPAGSATAAPCAPHP
  APRSRHHLKGSREGKEGEQIWFPKCWIPSPKKQPPRHSQTLPRPWAPGGTGWRESLGLGE
  GAGPETLEGWKATRRAHTLPRSSQGLSRGEGVFVIDATCVVIRSQYVPTPRTQQVQLLPS
  GVTRVVGDSPSQSKPGKEEGEGATVFPSPCQKRLSSSRLLHQPGGGRGGEAEGGRPGDST
  LEERTFRILGLPAPEVNLRDAPTQPGSPEHQALGPAASGAQGRAEGSEVAVVQRRAGRGW
  ARTPGPYAGALREAVSRIRRHTAPDSDTDEAEELSVHSGSSDGSDTEAPGASWRNERTLP
  EVGNSSPEEDGKTAELSDSVGEILDVISQTEEVLFGVRDIRGTQQGNRKRQ
• Function: Promotes apoptosis of kidney glomerular podocytes. Podocytes are highly specialized cells essential to the ultrafiltration of blood, resulting in the extraction of urine and the retention of protein.
• Tissue Specificity: Specifically expressed in brain and kidney. Expressed in kidney glomerular capillary loops (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephropathy	DISXWP4P	Definitive	Biomarker	[1]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Altered Expression	[2]
IgA nephropathy	DISZ8MTK	Strong	Altered Expression	[2]
Macular corneal dystrophy	DISOLD0H	Strong	Altered Expression	[2]
Nephrotic syndrome	DISSPSC2	Strong	Biomarker	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[4]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[5]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
GDC0941	DM1YAK6	Phase 2	Dendrin (DDN) increases the response to substance of GDC0941.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Dendrin (DDN).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dendrin (DDN).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dendrin (DDN).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Dendrin (DDN).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Dendrin (DDN).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dendrin (DDN).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dendrin (DDN).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Dendrin (DDN).	[16]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Dendrin (DDN).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Dendrin (DDN).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Dendrin (DDN).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Dendrin (DDN).	[13]

References

• [1] Nuclear relocation of the nephrin and CD2AP-binding protein dendrin promotes apoptosis of podocytes.Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10134-9. doi: 10.1073/pnas.0700917104. Epub 2007 May 30.
• [2] Expression of DENDRIN in several glomerular diseases and correlation to pathological parameters and renal failure - preliminary study.Diagn Pathol. 2018 Nov 20;13(1):90. doi: 10.1186/s13000-018-0767-z.
• [3] Dendrin expression in glomerulogenesis and in human minimal change nephrotic syndrome.Nephrol Dial Transplant. 2008 Aug;23(8):2504-11. doi: 10.1093/ndt/gfn100. Epub 2008 Mar 20.
• [4] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [5] Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.Hum Mol Genet. 2016 Aug 1;25(15):3383-3394. doi: 10.1093/hmg/ddw181. Epub 2016 Jun 21.
• [6] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] 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.
• [11] 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.
• [12] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [13] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [14] 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.
• [15] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [16] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [17] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [18] Modulators of sensitivity and resistance to inhibition of PI3K identified in a pharmacogenomic screen of the NCI-60 human tumor cell line collection. PLoS One. 2012;7(9):e46518. doi: 10.1371/journal.pone.0046518. Epub 2012 Sep 28.