Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP5E23B)

• DOT Name: Zinc finger protein ZIC 1
• Synonyms: Zinc finger protein 201; Zinc finger protein of the cerebellum 1
• Gene Name: ZIC1
• Related Disease:
  Craniosynostosis 6
  Structural brain anomalies with impaired intellectual development and craniosynostosis
  Isolated oxycephaly
  Obsolete isolated brachycephaly
  Obsolete isolated plagiocephaly
  Dandy-Walker syndrome
• UniProt ID: ZIC1_HUMAN
• Pfam ID: PF00096 ; PF18366
• Sequence:
  MLLDAGPQYPAIGVTTFGASRHHSAGDVAERDVGLGINPFADGMGAFKLNPSSHELASAG
  QTAFTSQAPGYAAAAALGHHHHPGHVGSYSSAAFNSTRDFLFRNRGFGDAAAAASAQHSL
  FAASAGGFGGPHGHTDAAGHLLFPGLHEQAAGHASPNVVNGQMRLGFSGDMYPRPEQYGQ
  VTSPRSEHYAAPQLHGYGPMNVNMAAHHGAGAFFRYMRQPIKQELICKWIEPEQLANPKK
  SCNKTFSTMHELVTHVTVEHVGGPEQSNHICFWEECPREGKPFKAKYKLVNHIRVHTGEK
  PFPCPFPGCGKVFARSENLKIHKRTHTGEKPFKCEFEGCDRRFANSSDRKKHMHVHTSDK
  PYLCKMCDKSYTHPSSLRKHMKVHESSSQGSQPSPAASSGYESSTPPTIVSPSTDNPTTS
  SLSPSSSAVHHTAGHSALSSNFNEWYV
• Function: Acts as a transcriptional activator. Involved in neurogenesis. Plays important roles in the early stage of organogenesis of the CNS, as well as during dorsal spinal cord development and maturation of the cerebellum. Involved in the spatial distribution of mossy fiber (MF) neurons within the pontine gray nucleus (PGN). Plays a role in the regulation of MF axon pathway choice. Promotes MF migration towards ipsilaterally-located cerebellar territories. May have a role in shear flow mechanotransduction in osteocytes. Retains nuclear GLI1 and GLI3 in the cytoplasm. Binds to the minimal GLI-consensus sequence 5'-TGGGTGGTC-3'.
• Tissue Specificity: CNS. A high level expression is seen in the cerebellum. Detected in the nuclei of the cerebellar granule cell lineage from the progenitor cells of the external germinal layer to the postmigrated cells of the internal granular layer. Detected in medulloblastoma (26/29 cases), but not present in all other tumors examined.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Craniosynostosis 6	DISMDB0M	Definitive	Autosomal dominant	[1]
Structural brain anomalies with impaired intellectual development and craniosynostosis	DISXRX3R	Strong	Autosomal dominant	[2]
Isolated oxycephaly	DISFXRXN	Supportive	Autosomal dominant	[2]
Obsolete isolated brachycephaly	DIS39ZDS	Supportive	Autosomal dominant	[2]
Obsolete isolated plagiocephaly	DISSZTKC	Supportive	Autosomal dominant	[2]
Dandy-Walker syndrome	DIS4HC6W	Limited	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cyclophosphamide	DM4O2Z7	Approved	Zinc finger protein ZIC 1 affects the response to substance of Cyclophosphamide.	[11]

1 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 Zinc finger protein ZIC 1.	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Zinc finger protein ZIC 1.	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Zinc finger protein ZIC 1.	[6]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Zinc finger protein ZIC 1.	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Zinc finger protein ZIC 1.	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Zinc finger protein ZIC 1.	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Zinc finger protein ZIC 1.	[9]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Zinc finger protein ZIC 1.	[10]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Gain-of-Function Mutations in ZIC1 Are Associated with Coronal Craniosynostosis and Learning Disability. Am J Hum Genet. 2015 Sep 3;97(3):378-88. doi: 10.1016/j.ajhg.2015.07.007.
• [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] 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.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [7] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [10] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [11] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.