Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOV8S81)

• DOT Name: Growth/differentiation factor 5 (GDF5)
• Synonyms: GDF-5; Bone morphogenetic protein 14; BMP-14; Cartilage-derived morphogenetic protein 1; CDMP-1; Lipopolysaccharide-associated protein 4; LAP-4; LPS-associated protein 4; Radotermin
• Gene Name: GDF5
• Related Disease:
  Acromesomelic dysplasia 2A
  Acromesomelic dysplasia 2B
  Acromesomelic dysplasia 2C, Hunter-Thompson type
  Brachydactyly type C
  Proximal symphalangism 1A
  Brachydactyly type A1C
  Symphalangism, proximal, 1B
  Angel-shaped phalango-epiphyseal dysplasia
  Brachydactyly type A1
  Brachydactyly type A2
  Multiple synostoses syndrome
  Proximal symphalangism
• UniProt ID: GDF5_HUMAN
• PDB ID: 1WAQ; 2BHK; 3EVS; 3QB4; 5HK5; 6Z3G; 6Z3H; 6Z3J; 6Z3L; 6Z3M; 7ZJF; 8E3G
• Pfam ID: PF00019 ; PF00688
• Sequence:
  MRLPKLLTFLLWYLAWLDLEFICTVLGAPDLGQRPQGTRPGLAKAEAKERPPLARNVFRP
  GGHSYGGGATNANARAKGGTGQTGGLTQPKKDEPKKLPPRPGGPEPKPGHPPQTRQATAR
  TVTPKGQLPGGKAPPKAGSVPSSFLLKKAREPGPPREPKEPFRPPPITPHEYMLSLYRTL
  SDADRKGGNSSVKLEAGLANTITSFIDKGQDDRGPVVRKQRYVFDISALEKDGLLGAELR
  ILRKKPSDTAKPAAPGGGRAAQLKLSSCPSGRQPAALLDVRSVPGLDGSGWEVFDIWKLF
  RNFKNSAQLCLELEAWERGRAVDLRGLGFDRAARQVHEKALFLVFGRTKKRDLFFNEIKA
  RSGQDDKTVYEYLFSQRRKRRAPLATRQGKRPSKNLKARCSRKALHVNFKDMGWDDWIIA
  PLEYEAFHCEGLCEFPLRSHLEPTNHAVIQTLMNSMDPESTPPTCCVPTRLSPISILFID
  SANNVVYKQYEDMVVESCGCR
• Function: Growth factor involved in bone and cartilage formation. During cartilage development regulates differentiation of chondrogenic tissue through two pathways. Firstly, positively regulates differentiation of chondrogenic tissue through its binding of high affinity with BMPR1B and of less affinity with BMPR1A, leading to induction of SMAD1-SMAD5-SMAD8 complex phosphorylation and then SMAD protein signaling transduction. Secondly, negatively regulates chondrogenic differentiation through its interaction with NOG. Required to prevent excessive muscle loss upon denervation. This function requires SMAD4 and is mediated by phosphorylated SMAD1/5/8. Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes.
• Tissue Specificity: Predominantly expressed in long bones during embryonic development. Expressed in monocytes (at protein level).
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  TGF-beta sig.ling pathway (hsa04350)
  Hippo sig.ling pathway (hsa04390)
• Reactome Pathway: Molecules associated with elastic fibres (R-HSA-2129379)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acromesomelic dysplasia 2A	DISISMZZ	Definitive	Autosomal recessive	[1]
Acromesomelic dysplasia 2B	DISSQNHW	Definitive	Autosomal recessive	[1]
Acromesomelic dysplasia 2C, Hunter-Thompson type	DISLUZV7	Definitive	Autosomal recessive	[2]
Brachydactyly type C	DISZ8FTZ	Definitive	Semidominant	[3]
Proximal symphalangism 1A	DIS1WSKZ	Definitive	Autosomal dominant	[4]
Brachydactyly type A1C	DISG8OS2	Strong	Autosomal dominant	[5]
Symphalangism, proximal, 1B	DISC4MN5	Strong	Autosomal dominant	[6]
Angel-shaped phalango-epiphyseal dysplasia	DIS12N7F	Supportive	Autosomal dominant	[7]
Brachydactyly type A1	DISZUO15	Supportive	Autosomal dominant	[8]
Brachydactyly type A2	DISUB1OU	Supportive	Autosomal dominant	[9]
Multiple synostoses syndrome	DISGA3UA	Supportive	Autosomal dominant	[10]
Proximal symphalangism	DISK9LH5	Supportive	Autosomal dominant	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Growth/differentiation factor 5 (GDF5).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Growth/differentiation factor 5 (GDF5).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Growth/differentiation factor 5 (GDF5).	[13]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Growth/differentiation factor 5 (GDF5).	[14]
Berberine	DMC5Q8X	Phase 4	Berberine decreases the expression of Growth/differentiation factor 5 (GDF5).	[15]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Growth/differentiation factor 5 (GDF5).	[16]

References

• [1] Du Pan syndrome phenotype caused by heterozygous pathogenic mutations in CDMP1 gene. Am J Med Genet A. 2005 Nov 1;138(4):379-83. doi: 10.1002/ajmg.a.30969.
• [2] A severe autosomal recessive acromesomelic dysplasia, the Hunter-Thompson type, and comparison with the Grebe type. Hum Genet. 1989 Mar;81(4):323-8. doi: 10.1007/BF00283684.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis. Nat Genet. 1999 Mar;21(3):302-4. doi: 10.1038/6821.
• [5] The mutational spectrum of brachydactyly type C. Am J Med Genet. 2002 Oct 15;112(3):291-6. doi: 10.1002/ajmg.10777.
• [6] Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2. J Clin Invest. 2005 Sep;115(9):2373-81. doi: 10.1172/JCI25118. Epub 2005 Aug 25.
• [7] Angel shaped phalangeal dysplasia, hip dysplasia, and positional teeth abnormalities are part of the brachydactyly C spectrum associated with CDMP-1 mutations. J Med Genet. 2004 Jun;41(6):e78. doi: 10.1136/jmg.2003.013904.
• [8] Mutations in GDF5 presenting as semidominant brachydactyly A1. Hum Mutat. 2010 Oct;31(10):1155-62. doi: 10.1002/humu.21338.
• [9] A mutation in the receptor binding site of GDF5 causes Mohr-Wriedt brachydactyly type A2. J Med Genet. 2006 Mar;43(3):225-31. doi: 10.1136/jmg.2005.034058. Epub 2005 Jul 13.
• [10] GDF5 is a second locus for multiple-synostosis syndrome. Am J Hum Genet. 2006 Apr;78(4):708-12. doi: 10.1086/503204. Epub 2006 Feb 24.
• [11] Novel point mutations in GDF5 associated with two distinct limb malformations in Chinese: brachydactyly type C and proximal symphalangism. J Hum Genet. 2008;53(4):368-374. doi: 10.1007/s10038-008-0253-7. Epub 2008 Feb 19.
• [12] 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.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Modulatory effects of inflammation and therapy on GDF-5 expression in rheumatoid arthritis synovium. Scand J Rheumatol. 2008 Nov-Dec;37(6):401-9. doi: 10.1080/03009740802120010.
• [15] Berberine promotes bone marrow-derived mesenchymal stem cells osteogenic differentiation via canonical Wnt/-catenin signaling pathway. Toxicol Lett. 2016 Jan 5;240(1):68-80. doi: 10.1016/j.toxlet.2015.10.007. Epub 2015 Oct 22.
• [16] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [17] 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.