Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU9C2EH)

• DOT Name: Protocadherin-15 (PCDH15)
• Gene Name: PCDH15
• Related Disease:
  Autism
  Autosomal recessive nonsyndromic hearing loss 23
  Usher syndrome type 1
  Usher syndrome type 1F
  Bipolar disorder
  Blindness
  Chronic obstructive pulmonary disease
  Deafness
  Drug dependence
  Hyperlipidemia, familial combined, LPL related
  Major depressive disorder
  Pituitary adenoma
  Retinitis pigmentosa
  Rheumatoid arthritis
  Sensorineural hearing loss disorder
  Substance abuse
  Substance dependence
  Usher syndrome type 1D
  Acute myelogenous leukaemia
  Isolated congenital microcephaly
  Hearing loss, autosomal recessive
  Nonsyndromic genetic hearing loss
  Usher syndrome
  Usher syndrome type 2D
  Usher syndrome type 3
• UniProt ID: PCD15_HUMAN
• PDB ID: 4XHZ; 5T4M; 5T4N; 5ULY; 6E8F; 6EB5; 6MFO; 6N2E
• Pfam ID: PF00028 ; PF18432
• Sequence:
  MFRQFYLWTCLASGIILGSLFEICLGQYDDDCKLARGGPPATIVAIDEESRNGTILVDNM
  LIKGTAGGPDPTIELSLKDNVDYWVLMDPVKQMLFLNSTGRVLDRDPPMNIHSIVVQVQC
  INKKVGTIIYHEVRIVVRDRNDNSPTFKHESYYATVNELTPVGTTIFTGFSGDNGATDID
  DGPNGQIEYVIQYNPDDPTSNDTFEIPLMLTGNIVLRKRLNYEDKTRYFVIIQANDRAQN
  LNERRTTTTTLTVDVLDGDDLGPMFLPCVLVPNTRDCRPLTYQAAIPELRTPEELNPIIV
  TPPIQAIDQDRNIQPPSDRPGILYSILVGTPEDYPRFFHMHPRTAELSLLEPVNRDFHQK
  FDLVIKAEQDNGHPLPAFAGLHIEILDENNQSPYFTMPSYQGYILESAPVGATISDSLNL
  TSPLRIVALDKDIEDTKDPELHLFLNDYTSVFTVTQTGITRYLTLLQPVDREEQQTYTFS
  ITAFDGVQESEPVIVNIQVMDANDNTPTFPEISYDVYVYTDMRPGDSVIQLTAVDADEGS
  NGEITYEILVGAQGDFIINKTTGLITIAPGVEMIVGRTYALTVQAADNAPPAERRNSICT
  VYIEVLPPNNQSPPRFPQLMYSLEISEAMRVGAVLLNLQATDREGDSITYAIENGDPQRV
  FNLSETTGILTLGKALDRESTDRYILIITASDGRPDGTSTATVNIVVTDVNDNAPVFDPY
  LPRNLSVVEEEANAFVGQVKATDPDAGINGQVHYSLGNFNNLFRITSNGSIYTAVKLNRE
  VRDYYELVVVATDGAVHPRHSTLTLAIKVLDIDDNSPVFTNSTYTVLVEENLPAGTTILQ
  IEAKDVDLGANVSYRIRSPEVKHFFALHPFTGELSLLRSLDYEAFPDQEASITFLVEAFD
  IYGTMPPGIATVTVIVKDMNDYPPVFSKRIYKGMVAPDAVKGTPITTVYAEDADPPGLPA
  SRVRYRVDDVQFPYPASIFEVEEDSGRVITRVNLNEEPTTIFKLVVVAFDDGEPVMSSSA
  TVKILVLHPGEIPRFTQEEYRPPPVSELATKGTMVGVISAAAINQSIVYSIVSGNEEDTF
  GINNITGVIYVNGPLDYETRTSYVLRVQADSLEVVLANLRVPSKSNTAKVYIEIQDENNH
  PPVFQKKFYIGGVSEDARMFTSVLRVKATDKDTGNYSVMAYRLIIPPIKEGKEGFVVETY
  TGLIKTAMLFHNMRRSYFKFQVIATDDYGKGLSGKADVLVSVVNQLDMQVIVSNVPPTLV
  EKKIEDLTEILDRYVQEQIPGAKVVVESIGARRHGDAFSLEDYTKCDLTVYAIDPQTNRA
  IDRNELFKFLDGKLLDINKDFQPYYGEGGRILEIRTPEAVTSIKKRGESLGYTEGALLAL
  AFIIILCCIPAILVVLVSYRQFKVRQAECTKTARIQAALPAAKPAVPAPAPVAAPPPPPP
  PPPGAHLYEELGDSSILFLLYHFQQSRGNNSVSEDRKHQQVVMPFSSNTIEAHKSAHVDG
  SLKSNKLKSARKFTFLSDEDDLSAHNPLYKENISQVSTNSDISQRTDFVDPFSPKIQAKS
  KSLRGPREKIQRLWSQSVSLPRRLMRKVPNRPEIIDLQQWQGTRQKAENENTGICTNKRG
  SSNPLLTTEEANLTEKEEIRQGETLMIEGTEQLKSLSSDSSFCFPRPHFSFSTLPTVSRT
  VELKSEPNVISSPAECSLELSPSRPCVLHSSLSRRETPICMLPIETERNIFENFAHPPNI
  SPSACPLPPPPPISPPSPPPAPAPLAPPPDISPFSLFCPPPSPPSIPLPLPPPTFFPLSV
  STSGPPTPPLLPPFPTPLPPPPPSIPCPPPPSASFLSTECVCITGVKCTTNLMPAEKIKS
  SMTQLSTTTVCKTDPQREPKGILRHVKNLAELEKSVANMYSQIEKNYLRTNVSELQTMCP
  SEVTNMEITSEQNKGSLNNIVEGTEKQSHSQSTSL
• Function: Calcium-dependent cell-adhesion protein. Essential for maintenance of normal retinal and cochlear function.
• Tissue Specificity: Expressed in brain, lung, kidney, spleen and testis. Found also in the inner and outer synaptic layers, and the nerve fiber layer in adult and fetal retinas. Found in the supporting cells, outer sulcus cells and spiral ganglion of fetal cochlea. Expressed in cytotoxic tumor-derived T- and NK-cell lines as well as biopsies of nasal NK/T-cell lymphomas. Not detected in normal or in vitro activated peripheral blood cells, CD4 or CD8 lymphocytes or NK cells. Isoform 3 is expressed in brain, heart, cerebellum and kidney. CD1 isoforms, such as isoform 1, have a limited pattern of expression and is detected in testis, retina and cochlea. CD2 isoforms, such as isoforms 4 and 5, are expressed in heart, kidney, thymus, spleen, testis, retina and cochlea. CD3 isoforms, such as isoform 6, are widely expressed.
• 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

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Definitive	Genetic Variation	[1]
Autosomal recessive nonsyndromic hearing loss 23	DISJHYGR	Definitive	Autosomal recessive	[2]
Usher syndrome type 1	DISR29E4	Definitive	Autosomal recessive	[3]
Usher syndrome type 1F	DISPDRVZ	Definitive	Autosomal recessive	[4]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[5]
Blindness	DISTIM10	Strong	Biomarker	[6]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[7]
Deafness	DISKCLH4	Strong	Genetic Variation	[8]
Drug dependence	DIS9IXRC	Strong	Biomarker	[9]
Hyperlipidemia, familial combined, LPL related	DISL1CE3	Strong	Genetic Variation	[10]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[5]
Pituitary adenoma	DISJ5R1X	Strong	Genetic Variation	[11]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[12]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[13]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[14]
Substance abuse	DIS327VW	Strong	Biomarker	[9]
Substance dependence	DISDRAAR	Strong	Biomarker	[9]
Usher syndrome type 1D	DISNK779	Strong	CausalMutation	[15]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[16]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[17]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[18]
Nonsyndromic genetic hearing loss	DISZX61P	Limited	Autosomal recessive	[3]
Usher syndrome	DIS9YIS7	Limited	Genetic Variation	[19]
Usher syndrome type 2D	DISHEVUD	Limited	Biomarker	[20]
Usher syndrome type 3	DISRAL84	Limited	Biomarker	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Protocadherin-15 (PCDH15) increases the Metabolic disorder ADR of Chlorothiazide.	[27]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protocadherin-15 (PCDH15).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protocadherin-15 (PCDH15).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Protocadherin-15 (PCDH15).	[25]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Protocadherin-15 (PCDH15).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Protocadherin-15 (PCDH15).	[22]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Protocadherin-15 (PCDH15).	[23]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Protocadherin-15 (PCDH15).	[23]

References

• [1] Individual common variants exert weak effects on the risk for autism spectrum disorders.Hum Mol Genet. 2012 Nov 1;21(21):4781-92. doi: 10.1093/hmg/dds301. Epub 2012 Jul 26.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 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] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [5] GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores.Am J Psychiatry. 2019 Aug 1;176(8):651-660. doi: 10.1176/appi.ajp.2019.18080957. Epub 2019 Jun 5.
• [6] Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygotes.J Med Genet. 2011 Nov;48(11):767-75. doi: 10.1136/jmedgenet-2011-100262. Epub 2011 Sep 22.
• [7] Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease.Am J Respir Cell Mol Biol. 2015 Aug;53(2):226-34. doi: 10.1165/rcmb.2014-0198OC.
• [8] Genetics of Usher Syndrome: New Insights From a Meta-analysis.Otol Neurotol. 2019 Jan;40(1):121-129. doi: 10.1097/MAO.0000000000002054.
• [9] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [10] A nonsynonymous SNP within PCDH15 is associated with lipid traits in familial combined hyperlipidemia.Hum Genet. 2010 Jan;127(1):83-9. doi: 10.1007/s00439-009-0749-z. Epub 2009 Oct 9.
• [11] Common variants at 10p12.31, 10q21.1 and 13q12.13 are associated with sporadic pituitary adenoma.Nat Genet. 2015 Jul;47(7):793-7. doi: 10.1038/ng.3322. Epub 2015 Jun 1.
• [12] Truncating variants in the majority of the cytoplasmic domain of PCDH15 are unlikely to cause Usher syndrome 1F.J Mol Diagn. 2014 Nov;16(6):673-8. doi: 10.1016/j.jmoldx.2014.07.001.
• [13] Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis.Pharmacogenomics J. 2013 Jun;13(3):235-41. doi: 10.1038/tpj.2012.8. Epub 2012 Apr 10.
• [14] Mutation in PCDH15 may modify the phenotypic expression of the 7511T>C mutation in MT-TS1 in a Chinese Han family with maternally inherited nonsyndromic hearing loss.Int J Pediatr Otorhinolaryngol. 2015 Oct;79(10):1654-7. doi: 10.1016/j.ijporl.2015.07.008. Epub 2015 Jul 11.
• [15] Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease.Ophthalmology. 2016 May;123(5):1143-50. doi: 10.1016/j.ophtha.2016.01.009. Epub 2016 Feb 9.
• [16] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [17] Causative novel PNKP mutations and concomitant PCDH15 mutations in a patient with microcephaly with early-onset seizures and developmental delay syndrome and hearing loss.J Hum Genet. 2014 Aug;59(8):471-4. doi: 10.1038/jhg.2014.51. Epub 2014 Jun 26.
• [18] 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.
• [19] 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.
• [20] Development of novel aminoglycoside (NB54) with reduced toxicity and enhanced suppression of disease-causing premature stop mutations.J Med Chem. 2009 May 14;52(9):2836-45. doi: 10.1021/jm801640k.
• [21] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [22] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [23] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [24] 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.
• [25] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [26] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [27] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.