Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4VOMBC)

• DOT Name: VPS10 domain-containing receptor SorCS3 (SORCS3)
• Gene Name: SORCS3
• Related Disease:
  Alzheimer disease
  Attention deficit hyperactivity disorder
  Cardiovascular disease
  Depression
  Intellectual disability
  Major depressive disorder
  Mood disorder
  Multiple sclerosis
  Schizophrenia
  West syndrome
  Complex neurodevelopmental disorder
  Mental disorder
• UniProt ID: SORC3_HUMAN
• Pfam ID: PF00801 ; PF15902 ; PF15901
• Sequence:
  MEAARTERPAGRPGAPLVRTGLLLLSTWVLAGAEITWDATGGPGRPAAPASRPPALSPLS
  PRAVASQWPEELASARRAAVLGRRAGPELLPQQGGGRGGEMQVEAGGTSPAGERRGRGIP
  APAKLGGARRSRRAQPPITQERGDAWATAPADGSRGSRPLAKGSREEVKAPRAGGSAAED
  LRLPSTSFALTGDSAHNQAMVHWSGHNSSVILILTKLYDFNLGSVTESSLWRSTDYGTTY
  EKLNDKVGLKTVLSYLYVNPTNKRKIMLLSDPEMESSILISSDEGATYQKYRLTFYIQSL
  LFHPKQEDWVLAYSLDQKLYSSMDFGRRWQLMHERITPNRFYWSVAGLDKEADLVHMEVR
  TTDGYAHYLTCRIQECAETTRSGPFARSIDISSLVVQDEYIFIQVTTSGRASYYVSYRRE
  AFAQIKLPKYSLPKDMHIISTDENQVFAAVQEWNQNDTYNLYISDTRGIYFTLAMENIKS
  SRGLMGNIIIELYEVAGIKGIFLANKKVDDQVKTYITYNKGRDWRLLQAPDVDLRGSPVH
  CLLPFCSLHLHLQLSENPYSSGRISSKETAPGLVVATGNIGPELSYTDIGVFISSDGGNT
  WRQIFDEEYNVWFLDWGGALVAMKHTPLPVRHLWVSFDEGHSWDKYGFTSVPLFVDGALV
  EAGMETHIMTVFGHFSLRSEWQLVKVDYKSIFSRHCTKEDYQTWHLLNQGEPCVMGERKI
  FKKRKPGAQCALGRDHSGSVVSEPCVCANWDFECDYGYERHGESQCVPAFWYNPASPSKD
  CSLGQSYLNSTGYRRIVSNNCTDGLREKYTAKAQMCPGKAPRGLHVVTTDGRLVAEQGHN
  ATFIILMEEGDLQRTNIQLDFGDGIAVSYANFSPIEDGIKHVYKSAGIFQVTAYAENNLG
  SDTAVLFLHVVCPVEHVHLRVPFVAIRNKEVNISAVVWPSQLGTLTYFWWFGNSTKPLIT
  LDSSISFTFLAEGTDTITVQVAAGNALIQDTKEIAVHEYFQSQLLSFSPNLDYHNPDIPE
  WRKDIGNVIKRALVKVTSVPEDQILIAVFPGLPTSAELFILPPKNLTERRKGNEGDLEQI
  VETLFNALNQNLVQFELKPGVQVIVYVTQLTLAPLVDSSAGHSSSAMLMLLSVVFVGLAV
  FLIYKFKRKIPWINIYAQVQHDKEQEMIGSVSQSENAPKITLSDFTEPEELLDKELDTRV
  IGGIATIANSESTKEIPNCTSV
• Tissue Specificity: Highly expressed in brain.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[2]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[3]
Depression	DIS3XJ69	Strong	Genetic Variation	[4]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[5]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[6]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[7]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[8]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[9]
West syndrome	DISLIAU9	Strong	Genetic Variation	[5]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[10]
Mental disorder	DIS3J5R8	Limited	Biomarker	[11]

5 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 VPS10 domain-containing receptor SorCS3 (SORCS3).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of VPS10 domain-containing receptor SorCS3 (SORCS3).	[13]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of VPS10 domain-containing receptor SorCS3 (SORCS3).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of VPS10 domain-containing receptor SorCS3 (SORCS3).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of VPS10 domain-containing receptor SorCS3 (SORCS3).	[17]

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 increases the methylation of VPS10 domain-containing receptor SorCS3 (SORCS3).	[16]

References

• [1] Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.
• [2] Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.Nat Genet. 2019 Jan;51(1):63-75. doi: 10.1038/s41588-018-0269-7. Epub 2018 Nov 26.
• [3] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [4] Exploring the sortilin related receptor, SorLA, in depression.J Affect Disord. 2018 May;232:260-267. doi: 10.1016/j.jad.2018.02.050. Epub 2018 Feb 21.
• [5] The SORCS3 gene is mutated in brothers with infantile spasms and intellectual disability.Discov Med. 2018 Oct;26(143):147-153.
• [6] Identification of common genetic risk variants for autism spectrum disorder.Nat Genet. 2019 Mar;51(3):431-444. doi: 10.1038/s41588-019-0344-8. Epub 2019 Feb 25.
• [7] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [8] Genetic analysis of the isolated Faroe Islands reveals SORCS3 as a potential multiple sclerosis risk gene.Mult Scler. 2016 May;22(6):733-40. doi: 10.1177/1352458515602338. Epub 2015 Sep 11.
• [9] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [10] 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.
• [11] Structural insights into SorCS2-Nerve Growth Factor complex formation.Nat Commun. 2018 Jul 30;9(1):2979. doi: 10.1038/s41467-018-05405-z.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [16] 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.
• [17] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.