Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNM60Y1)

• DOT Name: Chordin (CHRD)
• Gene Name: CHRD
• Related Disease:
  Holoprosencephaly
  Advanced cancer
  DiGeorge syndrome
  Fibrodysplasia ossificans progressiva
  Ovarian cancer
  Ovarian neoplasm
  Velocardiofacial syndrome
  Von willebrand disease
  Cornelia de Lange syndrome
  Thrombocytopenia
  Congenital heart disease
• UniProt ID: CHRD_HUMAN
• Pfam ID: PF07452 ; PF00093
• Sequence:
  MPSLPAPPAPLLLLGLLLLGSRPARGAGPEPPVLPIRSEKEPLPVRGAAGCTFGGKVYAL
  DETWHPDLGEPFGVMRCVLCACEAPQWGRRTRGPGRVSCKNIKPECPTPACGQPRQLPGH
  CCQTCPQERSSSERQPSGLSFEYPRDPEHRSYSDRGEPGAEERARGDGHTDFVALLTGPR
  SQAVARARVSLLRSSLRFSISYRRLDRPTRIRFSDSNGSVLFEHPAAPTQDGLVCGVWRA
  VPRLSLRLLRAEQLHVALVTLTHPSGEVWGPLIRHRALAAETFSAILTLEGPPQQGVGGI
  TLLTLSDTEDSLHFLLLFRGLLEPRSGGLTQVPLRLQILHQGQLLRELQANVSAQEPGFA
  EVLPNLTVQEMDWLVLGELQMALEWAGRPGLRISGHIAARKSCDVLQSVLCGADALIPVQ
  TGAAGSASLTLLGNGSLIYQVQVVGTSSEVVAMTLETKPQRRDQRTVLCHMAGLQPGGHT
  AVGICPGLGARGAHMLLQNELFLNVGTKDFPDGELRGHVAALPYCGHSARHDTLPVPLAG
  ALVLPPVKSQAAGHAWLSLDTHCHLHYEVLLAGLGGSEQGTVTAHLLGPPGTPGPRRLLK
  GFYGSEAQGVVKDLEPELLRHLAKGMASLMITTKGSPRGELRGQVHIANQCEVGGLRLEA
  AGAEGVRALGAPDTASAAPPVVPGLPALAPAKPGGPGRPRDPNTCFFEGQQRPHGARWAP
  NYDPLCSLCTCQRRTVICDPVVCPPPSCPHPVQAPDQCCPVCPEKQDVRDLPGLPRSRDP
  GEGCYFDGDRSWRAAGTRWHPVVPPFGLIKCAVCTCKGGTGEVHCEKVQCPRLACAQPVR
  VNPTDCCKQCPVGSGAHPQLGDPMQADGPRGCRFAGQWFPESQSWHPSVPPFGEMSCITC
  RCGAGVPHCERDDCSLPLSCGSGKESRCCSRCTAHRRPAPETRTDPELEKEAEGS
• Function: Dorsalizing factor. Key developmental protein that dorsalizes early vertebrate embryonic tissues by binding to ventralizing TGF-beta family bone morphogenetic proteins (BMPs) and sequestering them in latent complexes.
• Tissue Specificity: Expressed at the highest level in liver.
• KEGG Pathway: TGF-beta sig.ling pathway (hsa04350)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Holoprosencephaly	DISR35EC	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
DiGeorge syndrome	DIST1RKO	Strong	Biomarker	[3]
Fibrodysplasia ossificans progressiva	DISAT6WU	Strong	Altered Expression	[4]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[2]
Velocardiofacial syndrome	DISOSBTY	Strong	Biomarker	[3]
Von willebrand disease	DIS3TZCH	Strong	Genetic Variation	[5]
Cornelia de Lange syndrome	DISEQSXO	moderate	Altered Expression	[6]
Thrombocytopenia	DISU61YW	moderate	Altered Expression	[6]
Congenital heart disease	DISQBA23	Limited	Autosomal recessive	[7]

5 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 Chordin (CHRD).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Chordin (CHRD).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Chordin (CHRD).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Chordin (CHRD).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Chordin (CHRD).	[12]

2 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 Chordin (CHRD).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Chordin (CHRD).	[14]

References

• [1] Roles of bone morphogenetic protein signaling and its antagonism in holoprosencephaly.Am J Med Genet C Semin Med Genet. 2010 Feb 15;154C(1):43-51. doi: 10.1002/ajmg.c.30256.
• [2] Chordin is underexpressed in ovarian tumors and reduces tumor cell motility.FASEB J. 2006 Feb;20(2):240-50. doi: 10.1096/fj.05-4126com.
• [3] The role of chordin/Bmp signals in mammalian pharyngeal development and DiGeorge syndrome.Development. 2003 Aug;130(15):3567-78. doi: 10.1242/dev.00581.
• [4] Paresis of a bone morphogenetic protein-antagonist response in a genetic disorder of heterotopic skeletogenesis.J Bone Joint Surg Am. 2003 Apr;85(4):667-74. doi: 10.2106/00004623-200304000-00013.
• [5] Thrombospondin-1 (TSP-1), a new bone morphogenetic protein-2 and -4 (BMP-2/4) antagonist identified in pituitary cells.J Biol Chem. 2017 Sep 15;292(37):15352-15368. doi: 10.1074/jbc.M116.736207. Epub 2017 Jul 26.
• [6] Genomic organisation of the human chordin gene and mutation screening of candidate Cornelia de Lange syndrome genes.Hum Genet. 1999 Jul-Aug;105(1-2):104-11. doi: 10.1007/s004399900068.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] 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.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [13] 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.
• [14] 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.