Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8U28XD)

• DOT Name: PDZ domain-containing protein GIPC3 (GIPC3)
• Gene Name: GIPC3
• Related Disease:
  Nonsyndromic genetic hearing loss
  Autosomal recessive nonsyndromic hearing loss 15
  Deafness
  Sensorineural hearing loss disorder
  Hearing loss, autosomal recessive
• UniProt ID: GIPC3_HUMAN
• Pfam ID: PF00595
• Sequence:
  MEGAAAREARGTETPRASAPPPAPSEPPAAPRARPRLVFRTQLAHGSPTGKIEGFTNVRE
  LYAKIAEAFGIAPTEILFCTLNSHKVDMQKLLGGQIGLEDFIFAHVRGETKEVEVTKTED
  ALGLTITDNGAGYAFIKRIKEGSIINRIEAVCVGDSIEAINDHSIVGCRHYEVAKMLREL
  PKSQPFTLRLVQPKRAFDMIGQRSRSSKCPVEAKVTSGRETLRLRSGGAATVEEAPSEFE
  EEASRKVDDLLESYMGIRDPELASTMVETSKKTASAQEFARCLDSVLGEFAFPDEFVVEV
  WAAIGEAREACG
• Function: Required for postnatal maturation of the hair bundle and long-term survival of hair cells and spiral ganglion.
• Tissue Specificity: Widely expressed in adult and fetal tissues. Highest levels are found in jejunum, lymph node, parietal lobe, fetal spleen and fetal thymus. Expressed in cervical, melanoma, chronic myelogenous and gastric cancer cell lines.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nonsyndromic genetic hearing loss	DISZX61P	Definitive	Autosomal recessive	[1]
Autosomal recessive nonsyndromic hearing loss 15	DISMDTYM	Strong	Autosomal recessive	[2]
Deafness	DISKCLH4	Strong	Biomarker	[3]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[4]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of PDZ domain-containing protein GIPC3 (GIPC3).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of PDZ domain-containing protein GIPC3 (GIPC3).	[8]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of PDZ domain-containing protein GIPC3 (GIPC3).	[9]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of PDZ domain-containing protein GIPC3 (GIPC3).	[10]

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 PDZ domain-containing protein GIPC3 (GIPC3).	[7]

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] Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human. Nat Commun. 2011 Feb 15;2:201. doi: 10.1038/ncomms1200.
• [3] New gene for autosomal recessive non-syndromic hearing loss maps to either chromosome 3q or 19p.Am J Med Genet. 1997 Sep 5;71(4):467-71.
• [4] A novel missense mutation in GIPC3 causes sensorineural hearing loss in an Iranian family revealed by targeted next-generation sequencing.Int J Pediatr Otorhinolaryngol. 2018 May;108:8-11. doi: 10.1016/j.ijporl.2018.01.006. Epub 2018 Jan 31.
• [5] [Gene therapy for human hearing loss: challenges and promises]. Med Sci (Paris). 2013 Oct;29(10):883-9. doi: 10.1051/medsci/20132910016. Epub 2013 Oct 18.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [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] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [9] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [10] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.