Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOJGQ7S)

• DOT Name: Cadherin-23 (CDH23)
• Synonyms: Otocadherin
• Gene Name: CDH23
• Related Disease:
  Autosomal recessive nonsyndromic hearing loss 12
  Neural tube defect
  Nonsyndromic genetic hearing loss
  Usher syndrome type 1
  Usher syndrome type 1D
  Advanced cancer
  Alstrom syndrome
  Cerebellar ataxia
  Deafness
  Esophageal squamous cell carcinoma
  Lung adenocarcinoma
  Neoplasm
  Pituitary adenoma
  Pneumoconiosis
  Retinitis pigmentosa
  Usher syndrome type 2A
  Breast cancer
  Breast carcinoma
  Hearing loss, autosomal recessive
  Cushing disease
  Sensorineural hearing loss disorder
  Sickle-cell anaemia
  Systemic primary carnitine deficiency disease
  Usher syndrome
• UniProt ID: CAD23_HUMAN
• PDB ID: 2KBR; 2KBS; 2LSR; 5TFM; 5VVM; 5WJ8
• Pfam ID: PF00028
• Sequence:
  MGRHVATSCHVAWLLVLISGCWGQVNRLPFFTNHFFDTYLLISEDTPVGSSVTQLLAQDM
  DNDPLVFGVSGEEASRFFAVEPDTGVVWLRQPLDRETKSEFTVEFSVSDHQGVITRKVNI
  QVGDVNDNAPTFHNQPYSVRIPENTPVGTPIFIVNATDPDLGAGGSVLYSFQPPSQFFAI
  DSARGIVTVIRELDYETTQAYQLTVNATDQDKTRPLSTLANLAIIITDVQDMDPIFINLP
  YSTNIYEHSPPGTTVRIITAIDQDKGRPRGIGYTIVSGNTNSIFALDYISGVLTLNGLLD
  RENPLYSHGFILTVKGTELNDDRTPSDATVTTTFNILVIDINDNAPEFNSSEYSVAITEL
  AQVGFALPLFIQVVDKDENLGLNSMFEVYLVGNNSHHFIISPTSVQGKADIRIRVAIPLD
  YETVDRYDFDLFANESVPDHVGYAKVKITLINENDNRPIFSQPLYNISLYENVTVGTSVL
  TVLATDNDAGTFGEVSYFFSDDPDRFSLDKDTGLIMLIARLDYELIQRFTLTIIARDGGG
  EETTGRVRINVLDVNDNVPTFQKDAYVGALRENEPSVTQLVRLRATDEDSPPNNQITYSI
  VSASAFGSYFDISLYEGYGVISVSRPLDYEQISNGLIYLTVMAMDAGNPPLNSTVPVTIE
  VFDENDNPPTFSKPAYFVSVVENIMAGATVLFLNATDLDRSREYGQESIIYSLEGSTQFR
  INARSGEITTTSLLDRETKSEYILIVRAVDGGVGHNQKTGIATVNITLLDINDNHPTWKD
  APYYINLVEMTPPDSDVTTVVAVDPDLGENGTLVYSIQPPNKFYSLNSTTGKIRTTHAML
  DRENPDPHEAELMRKIVVSVTDCGRPPLKATSSATVFVNLLDLNDNDPTFQNLPFVAEVL
  EGIPAGVSIYQVVAIDLDEGLNGLVSYRMPVGMPRMDFLINSSSGVVVTTTELDRERIAE
  YQLRVVASDAGTPTKSSTSTLTIHVLDVNDETPTFFPAVYNVSVSEDVPREFRVVWLNCT
  DNDVGLNAELSYFITGGNVDGKFSVGYRDAVVRTVVGLDRETTAAYMLILEAIDNGPVGK
  RHTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSILQLKATDADEGEFGRVWYR
  ILHGNHGNNFRIHVSNGLLMRGPRPLDRERNSSHVLIVEAYNHDLGPMRSSVRVIVYVED
  INDEAPVFTQQQYSRLGLRETAGIGTSVIVVQATDRDSGDGGLVNYRILSGAEGKFEIDE
  STGLIITVNYLDYETKTSYMMNVSATDQAPPFNQGFCSVYITLLNELDEAVQFSNASYEA
  AILENLALGTEIVRVQAYSIDNLNQITYRFNAYTSTQAKALFKIDAITGVITVQGLVDRE
  KGDFYTLTVVADDGGPKVDSTVKVYITVLDENDNSPRFDFTSDSAVSIPEDCPVGQRVAT
  VKAWDPDAGSNGQVVFSLASGNIAGAFEIVTTNDSIGEVFVARPLDREELDHYILQVVAS
  DRGTPPRKKDHILQVTILDINDNPPVIESPFGYNVSVNENVGGGTAVVQVRATDRDIGIN
  SVLSYYITEGNKDMAFRMDRISGEIATRPAPPDRERQSFYHLVATVEDEGTPTLSATTHV
  YVTIVDENDNAPMFQQPHYEVLLDEGPDTLNTSLITIQALDLDEGPNGTVTYAIVAGNIV
  NTFRIDRHMGVITAAKELDYEISHGRYTLIVTATDQCPILSHRLTSTTTVLVNVNDINDN
  VPTFPRDYEGPFEVTEGQPGPRVWTFLAHDRDSGPNGQVEYSIMDGDPLGEFVISPVEGV
  LRVRKDVELDRETIAFYNLTICARDRGMPPLSSTMLVGIRVLDINDNDPVLLNLPMNITI
  SENSPVSSFVAHVLASDADSGCNARLTFNITAGNRERAFFINATTGIVTVNRPLDRERIP
  EYKLTISVKDNPENPRIARRDYDLLLIFLSDENDNHPLFTKSTYQAEVMENSPAGTPLTV
  LNGPILALDADQDIYAVVTYQLLGAQSGLFDINSSTGVVTVRSGVIIDREAFSPPILELL
  LLAEDIGLLNSTAHLLITILDDNDNRPTFSPATLTVHLLENCPPGFSVLQVTATDEDSGL
  NGELVYRIEAGAQDRFLIHLVTGVIRVGNATIDREEQESYRLTVVATDRGTVPLSGTAIV
  TILIDDINDSRPEFLNPIQTVSVLESAEPGTVIANITAIDHDLNPKLEYHIVGIVAKDDT
  DRLVPNQEDAFAVNINTGSVMVKSPMNRELVATYEVTLSVIDNASDLPERSVSVPNAKLT
  VNVLDVNDNTPQFKPFGITYYMERILEGATPGTTLIAVAAVDPDKGLNGLVTYTLLDLVP
  PGYVQLEDSSAGKVIANRTVDYEEVHWLNFTVRASDNGSPPRAAEIPVYLEIVDINDNNP
  IFDQPSYQEAVFEDVPVGTIILTVTATDADSGNFALIEYSLGDGESKFAINPTTGDIYVL
  SSLDREKKDHYILTALAKDNPGDVASNRRENSVQVVIQVLDVNDCRPQFSKPQFSTSVYE
  NEPAGTSVITMMATDQDEGPNGELTYSLEGPGVEAFHVDMDSGLVTTQRPLQSYEKFSLT
  VVATDGGEPPLWGTTMLLVEVIDVNDNRPVFVRPPNGTILHIREEIPLRSNVYEVYATDK
  DEGLNGAVRYSFLKTAGNRDWEFFIIDPISGLIQTAQRLDRESQAVYSLILVASDLGQPV
  PYETMQPLQVALEDIDDNEPLFVRPPKGSPQYQLLTVPEHSPRGTLVGNVTGAVDADEGP
  NAIVYYFIAAGNEEKNFHLQPDGCLLVLRDLDREREAIFSFIVKASSNRSWTPPRGPSPT
  LDLVADLTLQEVRVVLEDINDQPPRFTKAEYTAGVATDAKVGSELIQVLALDADIGNNSL
  VFYSILAIHYFRALANDSEDVGQVFTMGSMDGILRTFDLFMAYSPGYFVVDIVARDLAGH
  NDTAIIGIYILRDDQRVKIVINEIPDRVRGFEEEFIHLLSNITGAIVNTDNVQFHVDKKG
  RVNFAQTELLIHVVNRDTNRILDVDRVIQMIDENKEQLRNLFRNYNVLDVQPAISVRLPD
  DMSALQMAIIVLAILLFLAAMLFVLMNWYYRTVHKRKLKAIVAGSAGNRGFIDIMDMPNT
  NKYSFDGANPVWLDPFCRNLELAAQAEHEDDLPENLSEIADLWNSPTRTHGTFGREPAAV
  KPDDDRYLRAAIQEYDNIAKLGQIIREGPIKGSLLKVVLEDYLRLKKLFAQRMVQKASSC
  HSSISELIQTELDEEPGDHSPGQGSLRFRHKPPVELKGPDGIHVVHGSTGTLLATDLNSL
  PEEDQKGLGRSLETLTAAEATAFERNARTESAKSTPLHKLRDVIMETPLEITEL
• Function: Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells. CDH23 is required for establishing and/or maintaining the proper organization of the stereocilia bundle of hair cells in the cochlea and the vestibule during late embryonic/early postnatal development. It is part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells. Required for normal hearing.
• Tissue Specificity: Particularly strong expression in the retina . Found also in the cochlea.
• Reactome Pathway:
  Sensory processing of sound by outer hair cells of the cochlea (R-HSA-9662361)
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive nonsyndromic hearing loss 12	DISQU2W3	Definitive	Autosomal recessive	[1]
Neural tube defect	DIS5J95E	Definitive	Genetic Variation	[2]
Nonsyndromic genetic hearing loss	DISZX61P	Definitive	Autosomal recessive	[3]
Usher syndrome type 1	DISR29E4	Definitive	Autosomal recessive	[3]
Usher syndrome type 1D	DISNK779	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Alstrom syndrome	DISFVX55	Strong	Genetic Variation	[5]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[6]
Deafness	DISKCLH4	Strong	Genetic Variation	[7]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[4]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Pituitary adenoma	DISJ5R1X	Strong	Genetic Variation	[8]
Pneumoconiosis	DISSJLBN	Strong	Biomarker	[9]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[10]
Usher syndrome type 2A	DIS7OJKJ	Strong	CausalMutation	[11]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[12]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[12]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[13]
Cushing disease	DISOG6P2	Limited	SusceptibilityMutation	[8]
Sensorineural hearing loss disorder	DISJV45Z	Limited	Genetic Variation	[14]
Sickle-cell anaemia	DIS5YNZB	Limited	Genetic Variation	[15]
Systemic primary carnitine deficiency disease	DIS9OPZ4	Limited	Genetic Variation	[15]
Usher syndrome	DIS9YIS7	Limited	Genetic Variation	[16]

2 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 Cadherin-23 (CDH23).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cadherin-23 (CDH23).	[22]

6 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 Cadherin-23 (CDH23).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cadherin-23 (CDH23).	[19]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Cadherin-23 (CDH23).	[20]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Cadherin-23 (CDH23).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cadherin-23 (CDH23).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cadherin-23 (CDH23).	[24]

References

• [1] Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. Am J Hum Genet. 2001 Jan;68(1):26-37. doi: 10.1086/316954. Epub 2000 Nov 21.
• [2] A unique methylation pattern co-segregates with neural tube defect statuses in Han Chinese pedigrees.Neurol Sci. 2017 Dec;38(12):2153-2164. doi: 10.1007/s10072-017-3132-1. Epub 2017 Oct 4.
• [3] 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.
• [4] The strong propensity of Cadherin-23 for aggregation inhibits cell migration.Mol Oncol. 2019 May;13(5):1092-1109. doi: 10.1002/1878-0261.12469. Epub 2019 Mar 19.
• [5] Triple Vectors Expand AAV Transfer Capacity in the Retina.Mol Ther. 2018 Feb 7;26(2):524-541. doi: 10.1016/j.ymthe.2017.11.019. Epub 2017 Dec 5.
• [6] A V1143F mutation in the neuronal-enriched isoform 2 of the PMCA pump is linked with ataxia.Neurobiol Dis. 2018 Jul;115:157-166. doi: 10.1016/j.nbd.2018.04.009. Epub 2018 Apr 12.
• [7] Genetics of Usher Syndrome: New Insights From a Meta-analysis.Otol Neurotol. 2019 Jan;40(1):121-129. doi: 10.1097/MAO.0000000000002054.
• [8] Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas.Am J Hum Genet. 2017 May 4;100(5):817-823. doi: 10.1016/j.ajhg.2017.03.011. Epub 2017 Apr 13.
• [9] Pathway analysis for a genome-wide association study of pneumoconiosis.Toxicol Lett. 2015 Jan 5;232(1):284-92. doi: 10.1016/j.toxlet.2014.10.028. Epub 2014 Nov 4.
• [10] Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.Sci Rep. 2019 Feb 4;9(1):1219. doi: 10.1038/s41598-018-38007-2.
• [11] Variable clinical features in patients with CDH23 mutations (USH1D-DFNB12).Otol Neurotol. 2004 Sep;25(5):699-706. doi: 10.1097/00129492-200409000-00009.
• [12] Cadherin-23 mediates heterotypic cell-cell adhesion between breast cancer epithelial cells and fibroblasts.PLoS One. 2012;7(3):e33289. doi: 10.1371/journal.pone.0033289. Epub 2012 Mar 7.
• [13] 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.
• [14] Discovery of CDH23 as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans.PLoS One. 2016 Oct 28;11(10):e0165680. doi: 10.1371/journal.pone.0165680. eCollection 2016.
• [15] CDH23 Related Hearing Loss: A New Genetic Risk Factor for Semicircular Canal Dehiscence?.Otol Neurotol. 2016 Dec;37(10):1583-1588. doi: 10.1097/MAO.0000000000001210.
• [16] Targeted next generation sequencing in Italian patients with Usher syndrome: phenotype-genotype correlations.Sci Rep. 2017 Nov 15;7(1):15681. doi: 10.1038/s41598-017-16014-z.
• [17] 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.
• [18] 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.
• [19] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [20] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [21] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [22] 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.
• [23] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [24] 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.