Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD3KGJK)

• DOT Name: Growth/differentiation factor 3 (GDF3)
• Synonyms: GDF-3
• Gene Name: GDF3
• Related Disease:
  Breast cancer
  Breast carcinoma
  Embryonal neoplasm
  Endometriosis
  Germ cell tumor
  Klippel-Feil syndrome
  Klippel-Feil syndrome 1, autosomal dominant
  Retinoblastoma
  Seminoma
  Coloboma
  Isolated anophthalmia-microphthalmia syndrome
  Microphthalmia, isolated, with coloboma
  Obsolete isolated Klippel-Feil syndrome
  Adult germ cell tumor
  Germ cell tumour
  Isolated microphthalmia 7
  Klippel-Feil syndrome 3, autosomal dominant
  Microphthalmia, isolated, with coloboma 6
  Non-insulin dependent diabetes
• UniProt ID: GDF3_HUMAN
• Pfam ID: PF00019
• Sequence:
  MLRFLPDLAFSFLLILALGQAVQFQEYVFLQFLGLDKAPSPQKFQPVPYILKKIFQDREA
  AATTGVSRDLCYVKELGVRGNVLRFLPDQGFFLYPKKISQASSCLQKLLYFNLSAIKERE
  QLTLAQLGLDLGPNSYYNLGPELELALFLVQEPHVWGQTTPKPGKMFVLRSVPWPQGAVH
  FNLLDVAKDWNDNPRKNFGLFLEILVKEDRDSGVNFQPEDTCARLRCSLHASLLVVTLNP
  DQCHPSRKRRAAIPVPKLSCKNLCHRHQLFINFRDLGWHKWIIAPKGFMANYCHGECPFS
  LTISLNSSNYAFMQALMHAVDPEIPQAVCIPTKLSPISMLYQDNNDNVILRHYEDMVVDE
  CGCG
• Function: Growth factor involved in early embryonic development and adipose-tissue homeostasis. During embryogenesis controls formation of anterior visceral endoderm and mesoderm and the establishment of anterior-posterior identity through a receptor complex comprising the receptor ACVR1B and the coreceptor CRIPTO. Regulates adipose-tissue homeostasis and energy balance under nutrient overload in part by signaling through the receptor complex based on ACVR1C and CRIPTO/Cripto.
• KEGG Pathway: Cytokine-cytokine receptor interaction (hsa04060)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Embryonal neoplasm	DIS5MQSB	Strong	Biomarker	[2]
Endometriosis	DISX1AG8	Strong	Altered Expression	[3]
Germ cell tumor	DIS62070	Strong	Altered Expression	[4]
Klippel-Feil syndrome	DISRVCYV	Strong	Biomarker	[5]
Klippel-Feil syndrome 1, autosomal dominant	DISKGBD8	Strong	Biomarker	[6]
Retinoblastoma	DISVPNPB	Strong	Altered Expression	[7]
Seminoma	DIS3J8LJ	Strong	Altered Expression	[8]
Coloboma	DISP39N5	moderate	Genetic Variation	[9]
Isolated anophthalmia-microphthalmia syndrome	DISA55ZA	Supportive	Autosomal dominant	[10]
Microphthalmia, isolated, with coloboma	DISLSEUJ	Supportive	Autosomal dominant	[10]
Obsolete isolated Klippel-Feil syndrome	DISI44BI	Supportive	Autosomal dominant	[10]
Adult germ cell tumor	DISJUCQ7	Limited	Genetic Variation	[11]
Germ cell tumour	DISOF3TK	Limited	Genetic Variation	[11]
Isolated microphthalmia 7	DISK9KYL	Limited	Autosomal dominant	[12]
Klippel-Feil syndrome 3, autosomal dominant	DISGDW99	Limited	Autosomal dominant	[13]
Microphthalmia, isolated, with coloboma 6	DISX7WZB	Limited	Autosomal dominant	[12]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Growth/differentiation factor 3 (GDF3) increases the Metabolic disorder ADR of Chlorothiazide.	[22]

7 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 Growth/differentiation factor 3 (GDF3).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Growth/differentiation factor 3 (GDF3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Growth/differentiation factor 3 (GDF3).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Growth/differentiation factor 3 (GDF3).	[18]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Growth/differentiation factor 3 (GDF3).	[18]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Growth/differentiation factor 3 (GDF3).	[19]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Growth/differentiation factor 3 (GDF3).	[21]

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 decreases the methylation of Growth/differentiation factor 3 (GDF3).	[20]

References

• [1] GDF3 inhibits the growth of breast cancer cells and promotes the apoptosis induced by Taxol.J Cancer Res Clin Oncol. 2012 Jun;138(6):1073-9. doi: 10.1007/s00432-012-1213-3. Epub 2012 Apr 10.
• [2] Retinoic acid represses a cassette of candidate pluripotency chromosome 12p genes during induced loss of human embryonal carcinoma tumorigenicity. Biochim Biophys Acta. 2005 Oct 15;1731(1):48-56. doi: 10.1016/j.bbaexp.2005.08.006. Epub 2005 Sep 1.
• [3] Expression pattern of stemness-related genes in human endometrial and endometriotic tissues.Mol Med. 2009 Nov-Dec;15(11-12):392-401. doi: 10.2119/molmed.2009.00068. Epub 2009 Aug 10.
• [4] Testicular mixed germ cell tumors: a morphological and immunohistochemical study using stem cell markers, OCT3/4, SOX2 and GDF3, with emphasis on morphologically difficult-to-classify areas.Mod Pathol. 2009 Aug;22(8):1066-74. doi: 10.1038/modpathol.2009.66. Epub 2009 Apr 24.
• [5] Rare variants in the notch signaling pathway describe a novel type of autosomal recessive Klippel-Feil syndrome. Am J Med Genet A. 2015 Nov;167A(11):2795-9. doi: 10.1002/ajmg.a.37263. Epub 2015 Aug 4.
• [6] Stratified whole genome linkage analysis of Chiari type I malformation implicates known Klippel-Feil syndrome genes as putative disease candidates.PLoS One. 2013 Apr 19;8(4):e61521. doi: 10.1371/journal.pone.0061521. Print 2013.
• [7] ACVR1C/SMAD2 signaling promotes invasion and growth in retinoblastoma.Oncogene. 2019 Mar;38(12):2056-2075. doi: 10.1038/s41388-018-0543-2. Epub 2018 Nov 6.
• [8] Down-regulation of stem cell genes, including those in a 200-kb gene cluster at 12p13.31, is associated with in vivo differentiation of human male germ cell tumors.Cancer Res. 2006 Jan 15;66(2):820-7. doi: 10.1158/0008-5472.CAN-05-2445.
• [9] The genetic architecture of microphthalmia, anophthalmia and coloboma. Eur J Med Genet. 2014 Aug;57(8):369-80. doi: 10.1016/j.ejmg.2014.05.002. Epub 2014 May 22.
• [10] Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies. Hum Mol Genet. 2010 Jan 15;19(2):287-98. doi: 10.1093/hmg/ddp496. Epub 2009 Oct 28.
• [11] Human STELLAR, NANOG, and GDF3 genes are expressed in pluripotent cells and map to chromosome 12p13, a hotspot for teratocarcinoma.Stem Cells. 2004;22(2):169-79. doi: 10.1634/stemcells.22-2-169.
• [12] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [13] A recurrent, non-penetrant sequence variant, p.Arg266Cys in Growth/Differentiation Factor 3 (GDF3) in a female with unilateral anophthalmia and skeletal anomalies. Am J Ophthalmol Case Rep. 2017 Jun 21;7:102-106. doi: 10.1016/j.ajoc.2017.06.006. eCollection 2017 Sep.
• [14] Programming of adipose tissue miR-483-3p and GDF-3 expression by maternal diet in type 2 diabetes.Cell Death Differ. 2012 Jun;19(6):1003-12. doi: 10.1038/cdd.2011.183. Epub 2012 Jan 6.
• [15] 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.
• [16] Retinoic acid represses a cassette of candidate pluripotency chromosome 12p genes during induced loss of human embryonal carcinoma tumorigenicity. Biochim Biophys Acta. 2005 Oct 15;1731(1):48-56. doi: 10.1016/j.bbaexp.2005.08.006. Epub 2005 Sep 1.
• [17] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [18] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [19] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [20] 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.
• [21] Paraquat affects the differentiation of neural stem cells and impairs the function of vascular endothelial cells: a study of molecular mechanism. Environ Toxicol. 2019 Apr;34(4):548-555. doi: 10.1002/tox.22723. Epub 2019 Jan 30.
• [22] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.