Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBEHD89)

• DOT Name: Cochlin (COCH)
• Synonyms: COCH-5B2
• Gene Name: COCH
• Related Disease:
  Nonsyndromic genetic hearing loss
  Autosomal dominant nonsyndromic hearing loss 13
  Autosomal dominant nonsyndromic hearing loss 9
  Autosomal recessive nonsyndromic hearing loss 2
  Hearing loss, autosomal recessive 110
  Meniere disease
  Recessive dystrophic epidermolysis bullosa
  Von willebrand disease
  Inner ear disease
  Autosomal dominant nonsyndromic hearing loss
  Glaucoma/ocular hypertension
• UniProt ID: COCH_HUMAN
• PDB ID: 1JBI
• Pfam ID: PF03815 ; PF00092
• Sequence:
  MSAAWIPALGLGVCLLLLPGPAGSEGAAPIAITCFTRGLDIRKEKADVLCPGGCPLEEFS
  VYGNIVYASVSSICGAAVHRGVISNSGGPVRVYSLPGRENYSSVDANGIQSQMLSRWSAS
  FTVTKGKSSTQEATGQAVSTAHPPTGKRLKKTPEKKTGNKDCKADIAFLIDGSFNIGQRR
  FNLQKNFVGKVALMLGIGTEGPHVGLVQASEHPKIEFYLKNFTSAKDVLFAIKEVGFRGG
  NSNTGKALKHTAQKFFTVDAGVRKGIPKVVVVFIDGWPSDDIEEAGIVAREFGVNVFIVS
  VAKPIPEELGMVQDVTFVDKAVCRNNGFFSYHMPNWFGTTKYVKPLVQKLCTHEQMMCSK
  TCYNSVNIAFLIDGSSSVGDSNFRLMLEFVSNIAKTFEISDIGAKIAAVQFTYDQRTEFS
  FTDYSTKENVLAVIRNIRYMSGGTATGDAISFTVRNVFGPIRESPNKNFLVIVTDGQSYD
  DVQGPAAAAHDAGITIFSVGVAWAPLDDLKDMASKPKESHAFFTREFTGLEPIVSDVIRG
  ICRDFLESQQ
• Function: Plays a role in the control of cell shape and motility in the trabecular meshwork.
• Tissue Specificity: Expressed in inner ear structures; the cochlea and the vestibule.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nonsyndromic genetic hearing loss	DISZX61P	Definitive	Autosomal dominant	[1]
Autosomal dominant nonsyndromic hearing loss 13	DISFLETQ	Strong	Genetic Variation	[2]
Autosomal dominant nonsyndromic hearing loss 9	DISD5HDW	Strong	Autosomal dominant	[3]
Autosomal recessive nonsyndromic hearing loss 2	DIS1P51S	Strong	Genetic Variation	[2]
Hearing loss, autosomal recessive 110	DISPP7H7	Strong	Autosomal recessive	[4]
Meniere disease	DISC5R5F	Strong	Genetic Variation	[5]
Recessive dystrophic epidermolysis bullosa	DISVOPLZ	Strong	Genetic Variation	[6]
Von willebrand disease	DIS3TZCH	Strong	Genetic Variation	[7]
Inner ear disease	DISI6MRP	moderate	Genetic Variation	[8]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[9]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[10]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Cochlin (COCH) affects the response to substance of Fluorouracil.	[28]
Mitomycin	DMH0ZJE	Approved	Cochlin (COCH) affects the response to substance of Mitomycin.	[28]
Mitoxantrone	DMM39BF	Approved	Cochlin (COCH) affects the response to substance of Mitoxantrone.	[28]
Cyclophosphamide	DM4O2Z7	Approved	Cochlin (COCH) affects the response to substance of Cyclophosphamide.	[28]

19 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 Cochlin (COCH).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cochlin (COCH).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cochlin (COCH).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cochlin (COCH).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cochlin (COCH).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cochlin (COCH).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cochlin (COCH).	[17]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Cochlin (COCH).	[18]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Cochlin (COCH).	[19]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Cochlin (COCH).	[19]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of Cochlin (COCH).	[19]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of Cochlin (COCH).	[19]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Cochlin (COCH).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cochlin (COCH).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Cochlin (COCH).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cochlin (COCH).	[24]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Cochlin (COCH).	[25]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Cochlin (COCH).	[26]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Cochlin (COCH).	[27]

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 Cochlin (COCH).	[21]

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] Hereditary deafness and phenotyping in humans.Br Med Bull. 2002;63:73-94. doi: 10.1093/bmb/63.1.73.
• [3] High prevalence of symptoms of Menire's disease in three families with a mutation in the COCH gene. Hum Mol Genet. 1999 Aug;8(8):1425-9. doi: 10.1093/hmg/8.8.1425.
• [4] Hearing and vestibular deficits in the Coch(-/-) null mouse model: comparison to the Coch(G88E/G88E) mouse and to DFNA9 hearing and balance disorder. Hear Res. 2011 Feb;272(1-2):42-8. doi: 10.1016/j.heares.2010.11.002. Epub 2010 Nov 10.
• [5] Distinct vestibular phenotypes in DFNA9 families with COCH variants.Eur Arch Otorhinolaryngol. 2016 Oct;273(10):2993-3002. doi: 10.1007/s00405-015-3885-1. Epub 2016 Jan 13.
• [6] Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa.Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E705-E714. doi: 10.1073/pnas.1709111115. Epub 2018 Jan 5.
• [7] The second von Willebrand type A domain of cochlin has high affinity for type I, type II and type IV collagens.FEBS Lett. 2008 Dec 10;582(29):4003-7. doi: 10.1016/j.febslet.2008.10.050. Epub 2008 Nov 12.
• [8] Histopathology of the Human Inner Ear in the p.L114P COCH Mutation (DFNA9).Audiol Neurootol. 2016;21(2):88-97. doi: 10.1159/000443822. Epub 2016 Mar 30.
• [9] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [10] Cochlin in the eye: functional implications.Prog Retin Eye Res. 2007 Sep;26(5):453-69. doi: 10.1016/j.preteyeres.2007.06.002. Epub 2007 Jun 22.
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• [17] 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.
• [18] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
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• [20] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [21] 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.
• [22] 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.
• [23] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
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• [27] 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.
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