Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW3GX62)

• DOT Name: Protocadherin-16 (DCHS1)
• Synonyms: Cadherin-19; Cadherin-25; Fibroblast cadherin-1; Protein dachsous homolog 1
• Gene Name: DCHS1
• Related Disease:
  Mitral valve prolapse, myxomatous 2
  Narcolepsy
  Periventricular heterotopia with microcephaly, autosomal recessive
  Pituitary stalk interruption syndrome
  Van Maldergem syndrome 1
  Adult glioblastoma
  Glioblastoma multiforme
  Familial mitral valve prolapse
  Van Maldergem syndrome
  Mitral valve prolapse
  Periventricular nodular heterotopia
• UniProt ID: PCD16_HUMAN
• PDB ID: 8EGW; 8EGX
• Pfam ID: PF00028
• Sequence:
  MQKELGIVPSCPGMKSPRPHLLLPLLLLLLLLLGAGVPGAWGQAGSLDLQIDEEQPAGTL
  IGDISAGLPAGTAAPLMYFISAQEGSGVGTDLAIDEHSGVVRTARVLDREQRDRYRFTAV
  TPDGATVEVTVRVADINDHAPAFPQARAALQVPEHTAFGTRYPLEPARDADAGRLGTQGY
  ALSGDGAGETFRLETRPGPDGTPVPELVVTGELDRENRSHYMLQLEAYDGGSPPRRAQAL
  LDVTLLDINDHAPAFNQSRYHAVVSESLAPGSPVLQVFASDADAGVNGAVTYEINRRQSE
  GDGPFSIDAHTGLLQLERPLDFEQRRVHELVVQARDGGAHPELGSAFVTVHVRDANDNQP
  SMTVIFLSADGSPQVSEAAPPGQLVARISVSDPDDGDFAHVNVSLEGGEGHFALSTQDSV
  IYLVCVARRLDREERDAYNLRVTATDSGSPPLRAEAAFVLHVTDVNDNAPAFDRQLYRPE
  PLPEVALPGSFVVRVTARDPDQGTNGQVTYSLAPGAHTHWFSIDPTSGIITTAASLDYEL
  EPQPQLIVVATDGGLPPLASSATVSVALQDVNDNEPQFQRTFYNASLPEGTQPGTCFLQV
  TATDADSGPFGLLSYSLGAGLGSSGSPPFRIDAHSGDVCTTRTLDRDQGPSSFDFTVTAV
  DGGGLKSMVYVKVFLSDENDNPPQFYPREYAASISAQSPPGTAVLRLRAHDPDQGSHGRL
  SYHILAGNSPPLFTLDEQSGLLTVAWPLARRANSVVQLEIGAEDGGGLQAEPSARVDISI
  VPGTPTPPIFEQLQYVFSVPEDVAPGTSVGIVQAHNPPGRLAPVTLSLSGGDPRGLFSLD
  AVSGLLQTLRPLDRELLGPVLELEVRAGSGVPPAFAVARVRVLLDDVNDNSPAFPAPEDT
  VLLPPNTAPGTPIYTLRALDPDSGVNSRVTFTLLAGGGGAFTVDPTTGHVRLMRPLGPSG
  GPAHELELEARDGGSPPRTSHFRLRVVVQDVGTRGLAPRFNSPTYRVDLPSGTTAGTQVL
  QVQAQAPDGGPITYHLAAEGASSPFGLEPQSGWLWVRAALDREAQELYILKVMAVSGSKA
  ELGQQTGTATVRVSILNQNEHSPRLSEDPTFLAVAENQPPGTSVGRVFATDRDSGPNGRL
  TYSLQQLSEDSKAFRIHPQTGEVTTLQTLDREQQSSYQLLVQVQDGGSPPRSTTGTVHVA
  VLDLNDNSPTFLQASGAAGGGLPIQVPDRVPPGTLVTTLQAKDPDEGENGTILYTLTGPG
  SELFSLHPHSGELLTAAPLIRAERPHYVLTLSAHDQGSPPRSASLQLLVQVLPSARLAEP
  PPDLAERDPAAPVPVVLTVTAAEGLRPGSLLGSVAAPEPAGVGALTYTLVGGADPEGTFA
  LDAASGRLYLARPLDFEAGPPWRALTVRAEGPGGAGARLLRVQVQVQDENEHAPAFARDP
  LALALPENPEPGAALYTFRASDADGPGPNSDVRYRLLRQEPPVPALRLDARTGALSAPRG
  LDRETTPALLLLVEATDRPANASRRRAARVSARVFVTDENDNAPVFASPSRVRLPEDQPP
  GPAALHVVARDPDLGEAARVSYRLASGGDGHFRLHSSTGALSVVRPLDREQRAEHVLTVV
  ASDHGSPPRSATQVLTVSVADVNDEAPTFQQQEYSVLLRENNPPGTSLLTLRATDPDVGA
  NGQVTYGGVSSESFSLDPDTGVLTTLRALDREEQEEINLTVYAQDRGSPPQLTHVTVRVA
  VEDENDHAPTFGSAHLSLEVPEGQDPQTLTMLRASDPDVGANGQLQYRILDGDPSGAFVL
  DLASGEFGTMRPLDREVEPAFQLRIEARDGGQPALSATLLLTVTVLDANDHAPAFPVPAY
  SVEVPEDVPAGTLLLQLQAHDPDAGANGHVTYYLGAGTAGAFLLEPSSGELRTAAALDRE
  QCPSYTFSVSAVDGAAAGPLSTTVSVTITVRDVNDHAPTFPTSPLRLRLPRPGPSFSTPT
  LALATLRAEDRDAGANASILYRLAGTPPPGTTVDSYTGEIRVARSPVALGPRDRVLFIVA
  TDLGRPARSATGVIIVGLQGEAERGPRFPRASSEATIRENAPPGTPIVSPRAVHAGGTNG
  PITYSILSGNEKGTFSIQPSTGAITVRSAEGLDFEVSPRLRLVLQAESGGAFAFTVLTLT
  LQDANDNAPRFLRPHYVAFLPESRPLEGPLLQVEADDLDQGSGGQISYSLAASQPARGLF
  HVDPTTGTITTTAILDREIWAETRLVLMATDRGSPALVGSATLTVMVIDTNDNRPTIPQP
  WELRVSEDALLGSEIAQVTGNDVDSGPVLWYVLSPSGPQDPFSVGRYGGRVSLTGPLDFE
  QCDRYQLQLLAHDGPHEGRANLTVLVEDVNDNAPAFSQSLYQVMLLEHTPPGSAILSVSA
  TDRDSGANGHISYHLASPADGFSVDPNNGTLFTIVGTVALGHDGSGAVDVVLEARDHGAP
  GRAARATVHVQLQDQNDHAPSFTLSHYRVAVTEDLPPGSTLLTLEATDADGSRSHAAVDY
  SIISGNWGRVFQLEPRLAEAGESAGPGPRALGCLVLLEPLDFESLTQYNLTVAAADRGQP
  PQSSVVPVTVTVLDVNDNPPVFTRASYRVTVPEDTPVGAELLHVEASDADPGPHGLVRFT
  VSSGDPSGLFELDESSGTLRLAHALDCETQARHQLVVQAADPAGAHFALAPVTIEVQDVN
  DHGPAFPLNLLSTSVAENQPPGTLVTTLHAIDGDAGAFGRLRYSLLEAGPGPEGREAFAL
  NSSTGELRARVPFDYEHTESFRLLVGAADAGNLSASVTVSVLVTGEDEYDPVFLAPAFHF
  QVPEGARRGHSLGHVQATDEDGGADGLVLYSLATSSPYFGINQTTGALYLRVDSRAPGSG
  TATSGGGGRTRREAPRELRLEVIARGPLPGSRSATVPVTVDITHTALGLAPDLNLLLVGA
  VAASLGVVVVLALAALVLGLVRARSRKAEAAPGPMSQAAPLASDSLQKLGREPPSPPPSE
  HLYHQTLPSYGGPGAGGPYPRGGSLDPSHSSGRGSAEAAEDDEIRMINEFPRVASVASSL
  AARGPDSGIQQDADGLSDTSCEPPAPDTWYKGRKAGLLLPGAGATLYREEGPPATATAFL
  GGCGLSPAPTGDYGFPADGKPCVAGALTAIVAGEEELRGSYNWDYLLSWCPQFQPLASVF
  TEIARLKDEARPCPPAPRIDPPPLITAVAHPGAKSVPPKPANTAAARAIFPPASHRSPIS
  HEGSLSSAAMSPSFSPSLSPLAARSPVVSPFGVAQGPSASALSAESGLEPPDDTELHI
• Function: Calcium-dependent cell-adhesion protein. Mediates functions in neuroprogenitor cell proliferation and differentiation. In the heart, has a critical role for proper morphogenesis of the mitral valve, acting in the regulation of cell migration involved in valve formation.
• Tissue Specificity: Expressed in fibroblasts but not in melanocytes or keratinocytes.
• KEGG Pathway: Hippo sig.ling pathway - multiple species (hsa04392)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitral valve prolapse, myxomatous 2	DIS2TH8I	Strong	Autosomal dominant	[1]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[2]
Periventricular heterotopia with microcephaly, autosomal recessive	DISVEINW	Strong	Biomarker	[1]
Pituitary stalk interruption syndrome	DISGSN5T	Strong	Genetic Variation	[3]
Van Maldergem syndrome 1	DISH9F11	Strong	Autosomal recessive	[4]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[5]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[5]
Familial mitral valve prolapse	DIS1FAM4	Supportive	Autosomal dominant	[6]
Van Maldergem syndrome	DISV9YP7	Supportive	Autosomal recessive	[1]
Mitral valve prolapse	DISNCHQ3	Limited	Genetic Variation	[7]
Periventricular nodular heterotopia	DISU3ZRI	Limited	Genetic Variation	[8]

3 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 Protocadherin-16 (DCHS1).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Protocadherin-16 (DCHS1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protocadherin-16 (DCHS1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Protocadherin-16 (DCHS1).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Protocadherin-16 (DCHS1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protocadherin-16 (DCHS1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protocadherin-16 (DCHS1).	[15]

References

• [1] Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt cerebral cortical development. Nat Genet. 2013 Nov;45(11):1300-8. doi: 10.1038/ng.2765. Epub 2013 Sep 22.
• [2] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [3] Clues for Polygenic Inheritance of Pituitary Stalk Interruption Syndrome From Exome Sequencing in 20 Patients.J Clin Endocrinol Metab. 2018 Feb 1;103(2):415-428. doi: 10.1210/jc.2017-01660.
• [4] Clinical and neuroimaging findings in children with gray matter heterotopias: A single institution experience of 36 patients. Eur J Paediatr Neurol. 2016 Sep;20(5):732-7. doi: 10.1016/j.ejpn.2016.05.009. Epub 2016 May 25.
• [5] Myelin-forming cell-specific cadherin-19 is a marker for minimally infiltrative glioblastoma stem-like cells.J Neurosurg. 2015 Jan;122(1):69-77. doi: 10.3171/2014.9.JNS132373.
• [6] Mutations in DCHS1 cause mitral valve prolapse. Nature. 2015 Sep 3;525(7567):109-13. doi: 10.1038/nature14670. Epub 2015 Aug 10.
• [7] Deleterious variants in DCHS1 are prevalent in sporadic cases of mitral valve prolapse.Mol Genet Genomic Med. 2018 Jan;6(1):114-120. doi: 10.1002/mgg3.347. Epub 2017 Dec 10.
• [8] Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia.Nat Med. 2019 Apr;25(4):561-568. doi: 10.1038/s41591-019-0371-0. Epub 2019 Mar 11.
• [9] 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.
• [10] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [11] 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.
• [12] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [13] 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.
• [14] 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.
• [15] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.