Details of Drug Off-Target (DOT)

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

• DOT Name: Growth/differentiation factor 6 (GDF6)
• Synonyms: GDF-6; Bone morphogenetic protein 13; BMP-13; Growth/differentiation factor 16
• Gene Name: GDF6
• Related Disease:
  Klippel-Feil syndrome 1, autosomal dominant
  Melanoma
  Age-related macular degeneration
  Familial congenital mirror movements
  Inherited retinal dystrophy
  Intervertebral disc degeneration
  Knee osteoarthritis
  Microphthalmia
  Microphthalmia, isolated, with coloboma 6
  Multiple synostoses syndrome
  Multiple synostoses syndrome 4
  Neoplasm
  Spondylocostal dysostosis
  Sweetener
  Synostosis
  Synovial sarcoma
  Coloboma
  Leber congenital amaurosis
  Obsolete isolated Klippel-Feil syndrome
  Isolated microphthalmia 4
  Klippel-Feil syndrome
  Leber congenital amaurosis 17
  Septooptic dysplasia
• UniProt ID: GDF6_HUMAN
• Pfam ID: PF00019 ; PF00688
• Sequence:
  MDTPRVLLSAVFLISFLWDLPGFQQASISSSSSSAELGSTKGMRSRKEGKMQRAPRDSDA
  GREGQEPQPRPQDEPRAQQPRAQEPPGRGPRVVPHEYMLSIYRTYSIAEKLGINASFFQS
  SKSANTITSFVDRGLDDLSHTPLRRQKYLFDVSMLSDKEELVGAELRLFRQAPSAPWGPP
  AGPLHVQLFPCLSPLLLDARTLDPQGAPPAGWEVFDVWQGLRHQPWKQLCLELRAAWGEL
  DAGEAEARARGPQQPPPPDLRSLGFGRRVRPPQERALLVVFTRSQRKNLFAEMREQLGSA
  EAAGPGAGAEGSWPPPSGAPDARPWLPSPGRRRRRTAFASRHGKRHGKKSRLRCSKKPLH
  VNFKELGWDDWIIAPLEYEAYHCEGVCDFPLRSHLEPTNHAIIQTLMNSMDPGSTPPSCC
  VPTKLTPISILYIDAGNNVVYKQYEDMVVESCGCR
• Function: Growth factor that controls proliferation and cellular differentiation in the retina and bone formation. Plays a key role in regulating apoptosis during retinal development. Establishes dorsal-ventral positional information in the retina and controls the formation of the retinotectal map. Required for normal formation of bones and joints in the limbs, skull, digits and axial skeleton. Plays a key role in establishing boundaries between skeletal elements during development. Regulation of GDF6 expression seems to be a mechanism for evolving species-specific changes in skeletal structures. Seems to positively regulate differentiation of chondrogenic tissue through the growth factor receptors subunits BMPR1A, BMPR1B, BMPR2 and ACVR2A, leading to the activation of SMAD1-SMAD5-SMAD8 complex. The regulation of chondrogenic differentiation is inhibited by NOG. Also involved in the induction of adipogenesis from mesenchymal stem cells. This mechanism acts through the growth factor receptors subunits BMPR1A, BMPR2 and ACVR2A and the activation of SMAD1-SMAD5-SMAD8 complex and MAPK14/p38.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  TGF-beta sig.ling pathway (hsa04350)
  Hippo sig.ling pathway (hsa04390)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Klippel-Feil syndrome 1, autosomal dominant	DISKGBD8	Definitive	Autosomal dominant	[1]
Melanoma	DIS1RRCY	Definitive	Biomarker	[2]
Age-related macular degeneration	DIS0XS2C	Strong	Biomarker	[3]
Familial congenital mirror movements	DISJLV92	Strong	Genetic Variation	[4]
Inherited retinal dystrophy	DISGGL77	Strong	Biomarker	[5]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[6]
Knee osteoarthritis	DISLSNBJ	Strong	Biomarker	[7]
Microphthalmia	DISGEBES	Strong	Genetic Variation	[8]
Microphthalmia, isolated, with coloboma 6	DISX7WZB	Strong	Biomarker	[9]
Multiple synostoses syndrome	DISGA3UA	Strong	Genetic Variation	[10]
Multiple synostoses syndrome 4	DIS8N9I0	Strong	Autosomal dominant	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Spondylocostal dysostosis	DISTPWFK	Strong	Genetic Variation	[1]
Sweetener	DISDGALM	Strong	Biomarker	[12]
Synostosis	DISXGMZW	Strong	Genetic Variation	[10]
Synovial sarcoma	DISEZJS7	Strong	Biomarker	[12]
Coloboma	DISP39N5	moderate	Genetic Variation	[13]
Leber congenital amaurosis	DISMGH8F	Supportive	Autosomal dominant	[5]
Obsolete isolated Klippel-Feil syndrome	DISI44BI	Supportive	Autosomal dominant	[4]
Isolated microphthalmia 4	DISL94P1	Limited	Autosomal dominant	[4]
Klippel-Feil syndrome	DISRVCYV	Limited	Biomarker	[14]
Leber congenital amaurosis 17	DIS0THL0	Limited	Unknown	[4]
Septooptic dysplasia	DISXYR1H	Limited	Biomarker	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Growth/differentiation factor 6 (GDF6).	[16]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Growth/differentiation factor 6 (GDF6).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Growth/differentiation factor 6 (GDF6).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Growth/differentiation factor 6 (GDF6).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Growth/differentiation factor 6 (GDF6).	[18]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Growth/differentiation factor 6 (GDF6).	[20]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Growth/differentiation factor 6 (GDF6).	[21]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Growth/differentiation factor 6 (GDF6).	[23]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone decreases the expression of Growth/differentiation factor 6 (GDF6).	[24]

References

• [1] Incomplete penetrance and phenotypic variability characterize Gdf6-attributable oculo-skeletal phenotypes. Hum Mol Genet. 2009 Mar 15;18(6):1110-21. doi: 10.1093/hmg/ddp008. Epub 2009 Jan 6.
• [2] Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma.J Clin Invest. 2018 Jan 2;128(1):294-308. doi: 10.1172/JCI92513. Epub 2017 Dec 4.
• [3] Association of rs6982567 near GDF6 with neovascular age-related macular degeneration and polypoidal choroidal vasculopathy in a Han Chinese cohort.BMC Ophthalmol. 2014 Nov 22;14:140. doi: 10.1186/1471-2415-14-140.
• [4] Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome. Hum Mutat. 2008 Aug;29(8):1017-27. doi: 10.1002/humu.20741.
• [5] Contribution of growth differentiation factor 6-dependent cell survival to early-onset retinal dystrophies. Hum Mol Genet. 2013 Apr 1;22(7):1432-42. doi: 10.1093/hmg/dds560. Epub 2013 Jan 9.
• [6] ISSLS PRIZE IN BASIC SCIENCE 2018: Growth differentiation factor-6 attenuated pro-inflammatory molecular changes in the rabbit anular-puncture model and degenerated disc-induced pain generation in the rat xenograft radiculopathy model.Eur Spine J. 2018 Apr;27(4):739-751. doi: 10.1007/s00586-018-5488-1. Epub 2018 Feb 19.
• [7] Relationship between knee joint contact forces and external knee joint moments in patients with medial knee osteoarthritis: effects of gait modifications.Osteoarthritis Cartilage. 2018 Sep;26(9):1203-1214. doi: 10.1016/j.joca.2018.04.011. Epub 2018 Apr 30.
• [8] High temperature requirement factor A1 (HTRA1) gene regulates angiogenesis through transforming growth factor- family member growth differentiation factor 6.J Biol Chem. 2012 Jan 6;287(2):1520-6. doi: 10.1074/jbc.M111.275990. Epub 2011 Nov 2.
• [9] GDF6, a novel locus for a spectrum of ocular developmental anomalies.Am J Hum Genet. 2007 Feb;80(2):306-15. doi: 10.1086/511280. Epub 2006 Dec 29.
• [10] Further delineation of the GDF6 related multiple synostoses syndrome.Am J Med Genet A. 2018 Jan;176(1):225-229. doi: 10.1002/ajmg.a.38503. Epub 2017 Nov 12.
• [11] Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genes. Dev Biol. 2003 Feb 1;254(1):116-30. doi: 10.1016/s0012-1606(02)00022-2.
• [12] KISS1 over-expression suppresses metastasis of pancreatic adenocarcinoma in a xenograft mouse model.Clin Exp Metastasis. 2010 Dec;27(8):591-600. doi: 10.1007/s10585-010-9349-5. Epub 2010 Sep 16.
• [13] 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.
• [14] 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.
• [15] Improving disease gene prioritization by comparing the semantic similarity of phenotypes in mice with those of human diseases.PLoS One. 2012;7(6):e38937. doi: 10.1371/journal.pone.0038937. Epub 2012 Jun 14.
• [16] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [17] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
• [20] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [21] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [22] 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.
• [23] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.
• [24] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.