Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0NUJIZ)

• DOT Name: Sclerostin (SOST)
• Gene Name: SOST
• Related Disease:
  Sclerosteosis 1
  Craniodiaphyseal dysplasia
  Hyperostosis corticalis generalisata
  Craniodiaphyseal dysplasia, autosomal dominant
• UniProt ID: SOST_HUMAN
• PDB ID: 2K8P; 3SOV; 6L6R
• Pfam ID: PF05463
• Sequence:
  MQLPLALCLVCLLVHTAFRVVEGQGWQAFKNDATEIIPELGEYPEPPPELENNKTMNRAE
  NGGRPPHHPFETKDVSEYSCRELHFTRYVTDGPCRSAKPVTELVCSGQCGPARLLPNAIG
  RGKWWRPSGPDFRCIPDRYRAQRVQLLCPGGEAPRARKVRLVASCKCKRLTRFHNQSELK
  DFGTEAARPQKGRKPRPRARSAKANQAELENAY
• Function: Negative regulator of bone growth that acts through inhibition of Wnt signaling and bone formation.
• Tissue Specificity: Widely expressed at low levels with highest levels in bone, cartilage, kidney, liver, bone marrow and primary osteoblasts differentiated for 21 days. Detected in the subendothelial layer of the aortic intima (at protein level).
• KEGG Pathway:
  Wnt sig.ling pathway (hsa04310)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
• Reactome Pathway:
  Negative regulation of TCF-dependent signaling by WNT ligand antagonists (R-HSA-3772470)
  TCF dependent signaling in response to WNT (R-HSA-201681)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Sclerosteosis 1	DISHY0YW	Strong	Autosomal recessive	[1]
Craniodiaphyseal dysplasia	DIST8T27	Supportive	Autosomal dominant	[2]
Hyperostosis corticalis generalisata	DISR4BHB	Supportive	Autosomal dominant	[3]
Craniodiaphyseal dysplasia, autosomal dominant	DIS2YXJ1	Limited	Unknown	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Sclerostin (SOST).	[4]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Sclerostin (SOST).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Sclerostin (SOST).	[6]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Sclerostin (SOST).	[8]

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 affects the methylation of Sclerostin (SOST).	[7]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia. Hum Genet. 2011 May;129(5):497-502. doi: 10.1007/s00439-011-0947-3. Epub 2011 Jan 9.
• [3] Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet. 2002 Feb;39(2):91-7. doi: 10.1136/jmg.39.2.91.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [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] 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.
• [8] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.