Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSOW3MV)

• DOT Name: Protocadherin-19 (PCDH19)
• Gene Name: PCDH19
• Related Disease:
  Developmental and epileptic encephalopathy, 9
  X-linked complex neurodevelopmental disorder
  Autism
  Brain disease
  Childhood epilepsy with centrotemporal spikes
  Cognitive impairment
  Infantile epileptic-dyskinetic encephalopathy
  Klinefelter syndrome
  Pervasive developmental disorder
  Psychotic disorder
  Alcohol dependence
  Status epilepticus seizure
  Obsolete Dravet syndrome
  X-linked intellectual disability
  Advanced cancer
  Epilepsy syndrome
  Hepatocellular carcinoma
  Neurodevelopmental disorder
  Schizophrenia
• UniProt ID: PCD19_HUMAN
• PDB ID: 6VFU
• Pfam ID: PF00028 ; PF08266
• Sequence:
  MESLLLPVLLLLAILWTQAAALINLKYSVEEEQRAGTVIANVAKDAREAGFALDPRQASA
  FRVVSNSAPHLVDINPSSGLLVTKQKIDRDLLCRQSPKCIISLEVMSSSMEICVIKVEIK
  DLNDNAPSFPAAQIELEISEAASPGTRIPLDSAYDPDSGSFGVQTYELTPNELFGLEIKT
  RGDGSRFAELVVEKSLDRETQSHYSFRITALDGGDPPRLGTVGLSIKVTDSNDNNPVFSE
  STYAVSVPENSPPNTPVIRLNASDPDEGTNGQVVYSFYGYVNDRTRELFQIDPHSGLVTV
  TGALDYEEGHVYELDVQAKDLGPNSIPAHCKVTVSVLDTNDNPPVINLLSVNSELVEVSE
  SAPPGYVIALVRVSDRDSGLNGRVQCRLLGNVPFRLQEYESFSTILVDGRLDREQHDQYN
  LTIQARDGGVPMLQSAKSFTVLITDENDNHPHFSKPYYQVIVQENNTPGAYLLSVSARDP
  DLGLNGSVSYQIVPSQVRDMPVFTYVSINPNSGDIYALRSFNHEQTKAFEFKVLAKDGGL
  PSLQSNATVRVIILDVNDNTPVITAPPLINGTAEVYIPRNSGIGYLVTVVKAEDYDEGEN
  GRVTYDMTEGDRGFFEIDQVNGEVRTTRTFGESSKSSYELIVVAHDHGKTSLSASALVLI
  YLSPALDAQESMGSVNLSLIFIIALGSIAGILFVTMIFVAIKCKRDNKEIRTYNCSNCLT
  ITCLLGCFIKGQNSKCLHCISVSPISEEQDKKTEEKVSLRGKRIAEYSYGHQKKSSKKKK
  ISKNDIRLVPRDVEETDKMNVVSCSSLTSSLNYFDYHQQTLPLGCRRSESTFLNVENQNT
  RNTSANHIYHHSFNSQGPQQPDLIINGVPLPETENYSFDSNYVNSRAHLIKSSSTFKDLE
  GNSLKDSGHEESDQTDSEHDVQRSLYCDTAVNDVLNTSVTSMGSQMPDHDQNEGFHCREE
  CRILGHSDRCWMPRNPMPIRSKSPEHVRNIIALSIEATAADVEAYDDCGPTKRTFATFGK
  DVSDHPAEERPTLKGKRTVDVTICSPKVNSVIREAGNGCEAISPVTSPLHLKSSLPTKPS
  VSYTIALAPPARDLEQYVNNVNNGPTRPSEAEPRGADSEKVMHEVSPILKEGRNKESPGV
  KRLKDIVL
• Function: Calcium-dependent cell-adhesion protein.
• Tissue Specificity: Moderately expressed in all regions of the brain examined, with lowest levels found in the cerebellum. Moderate expression is also found in ovary, and low expression in all other tissues tested. Also detected in primary skin fibroblast.

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 9	DISR0ACD	Definitive	X-linked	[1]
X-linked complex neurodevelopmental disorder	DISI3QE9	Definitive	X-linked	[2]
Autism	DISV4V1Z	Strong	Altered Expression	[3]
Brain disease	DIS6ZC3X	Strong	Genetic Variation	[3]
Childhood epilepsy with centrotemporal spikes	DISKT2L5	Strong	CausalMutation	[4]
Cognitive impairment	DISH2ERD	Strong	Genetic Variation	[5]
Infantile epileptic-dyskinetic encephalopathy	DISD2ZNC	Strong	Biomarker	[6]
Klinefelter syndrome	DISOUI7W	Strong	Biomarker	[7]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[5]
Psychotic disorder	DIS4UQOT	Strong	Genetic Variation	[8]
Alcohol dependence	DIS4ZSCO	moderate	Biomarker	[9]
Status epilepticus seizure	DISY3BIC	moderate	Biomarker	[10]
Obsolete Dravet syndrome	DISM4LMK	Supportive	Autosomal dominant	[11]
X-linked intellectual disability	DISYJBY3	Disputed	Biomarker	[12]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[13]
Epilepsy syndrome	DISLYXJ3	Limited	Genetic Variation	[14]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[13]
Neurodevelopmental disorder	DIS372XH	Limited	Genetic Variation	[15]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[8]

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 Protocadherin-19 (PCDH19).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protocadherin-19 (PCDH19).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protocadherin-19 (PCDH19).	[17]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protocadherin-19 (PCDH19).	[18]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Protocadherin-19 (PCDH19).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Protocadherin-19 (PCDH19).	[20]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Protocadherin-19 (PCDH19).	[21]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protocadherin-19 (PCDH19).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protocadherin-19 (PCDH19).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protocadherin-19 (PCDH19).	[25]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] 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.
• [3] Autism-like behaviors in male mice with a Pcdh19 deletion.Mol Brain. 2019 Nov 20;12(1):95. doi: 10.1186/s13041-019-0519-3.
• [4] Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.Eur J Hum Genet. 2018 Feb;26(2):258-264. doi: 10.1038/s41431-017-0034-x. Epub 2018 Jan 22.
• [5] Autism spectrum disorder phenotype and intellectual disability in females with epilepsy and PCDH-19 mutations.Epilepsy Behav. 2016 Jul;60:75-80. doi: 10.1016/j.yebeh.2016.04.009. Epub 2016 May 12.
• [6] The Role of Protocadherin 19 (PCDH19) in Neurodevelopment and in the Pathophysiology of Early Infantile Epileptic Encephalopathy-9 (EIEE9).Dev Neurobiol. 2019 Jan;79(1):75-84. doi: 10.1002/dneu.22654. Epub 2019 Jan 18.
• [7] PCDH19-related epilepsy in a male with Klinefelter syndrome: Additional evidence supporting PCDH19 cellular interference disease mechanism.Epilepsy Res. 2018 Sep;145:89-92. doi: 10.1016/j.eplepsyres.2018.06.008. Epub 2018 Jun 18.
• [8] Schizophrenia is a later-onset feature of PCDH19 Girls Clustering Epilepsy.Epilepsia. 2019 Mar;60(3):429-440. doi: 10.1111/epi.14678. Epub 2019 Mar 3.
• [9] Cadherins and neuropsychiatric disorders.Brain Res. 2012 Aug 27;1470:130-44. doi: 10.1016/j.brainres.2012.06.020. Epub 2012 Jul 2.
• [10] The role of PCDH19 in refractory status epilepticus.Epilepsy Behav. 2019 Dec;101(Pt B):106539. doi: 10.1016/j.yebeh.2019.106539. Epub 2019 Oct 31.
• [11] Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet. 2009 Feb;5(2):e1000381. doi: 10.1371/journal.pgen.1000381. Epub 2009 Feb 13.
• [12] X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat Genet. 2008 Jun;40(6):776-81. doi: 10.1038/ng.149. Epub 2008 May 11.
• [13] Methylation of PCDH19 predicts poor prognosis of hepatocellular carcinoma.Asia Pac J Clin Oncol. 2018 Oct;14(5):e352-e358. doi: 10.1111/ajco.12982. Epub 2018 May 11.
• [14] Expression profile of N-cadherin and protocadherin-19 in postnatal mouse limbic structures.J Comp Neurol. 2018 Mar 1;526(4):663-680. doi: 10.1002/cne.24359. Epub 2017 Dec 3.
• [15] High frequency of mosaic pathogenic variants in genes causing epilepsy-related neurodevelopmental disorders.Genet Med. 2018 Apr;20(4):403-410. doi: 10.1038/gim.2017.114. Epub 2017 Aug 24.
• [16] 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.
• [17] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [18] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [19] Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells. Toxicol Appl Pharmacol. 2017 Sep 15;331:154-163.
• [20] 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.
• [21] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] 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.
• [24] 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.
• [25] 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.