Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX3VAOB)

• DOT Name: PDZ domain-containing protein 7 (PDZD7)
• Gene Name: PDZD7
• Related Disease:
  Hearing loss, autosomal recessive
  Usher syndrome type 2D
  Carcinoma of liver and intrahepatic biliary tract
  Deafness
  Hearing loss, autosomal recessive 57
  Hepatocellular carcinoma
  Liver cancer
  Retinitis pigmentosa
  Retinopathy
  Sensorineural hearing loss disorder
  Usher syndrome
  Usher syndrome type 2
  Usher syndrome type 2C
• UniProt ID: PDZD7_HUMAN
• PDB ID: 2EEH; 7PC5
• Pfam ID: PF00595
• Sequence:
  MAQGFAVGFDPLGLGDLSSGSLSSLSSRGHLGSDSGSTATRYLLRKQQRLLNGPPRGIRA
  SSPMGRVILINSPIEANSDESDIIHSVRVEKSPAGRLGFSVRGGSEHGLGIFVSKVEEGS
  SAERAGLCVGDKITEVNGLSLESTTMGSAVKVLTSSSRLHMMVRRMGRVPGIKFSKEKTT
  WVDVVNRRLVVEKCGSTPSDTSSEDGVRRIVHLYTTSDDFCLGFNIRGGKEFGLGIYVSK
  VDHGGLAEENGIKVGDQVLAANGVRFDDISHSQAVEVLKGQTHIMLTIKETGRYPAYKEM
  VSEYCWLDRLSNGVLQQLSPASESSSSVSSCASSAPYSSGSLPSDRMDICLGQEEPGSRG
  PGWGRADTAMQTEPDAGGRVETWCSVRPTVILRDTAIRSDGPHPGRRLDSALSESPKTAL
  LLALSRPRPPITRSQSYLTLWEEKQQRKKEKSGSPGEKGALQRSKTLMNLFFKGGRQGRL
  ARDGRREAWTLDSGSLAKTYPRLDIEKAGGVGPVQKFVTWRLRRDQERGRALLSARSGSP
  SSQLPNVDEQVQAWESRRPLIQDLAQRLLTDDEVLAVTRHCSRYVHEGGIEDLVRPLLAI
  LDRPEKLLLLQDIRSVVAPTDLGRFDSMVMLVELEAFEALKSRAVRPPALRPARQDTPPK
  RHLITPVPDSRGGFYLLPVNGFPEEEDNGELRERLGALKVSPSASAPRHPHKGIPPLQDV
  PVDAFTPLRIACTPPPQLPPVAPRPLRPNWLLTEPLSREHPPQSQIRGRAQSRSRSRSRS
  RSRSSRGQGKSPGRRSPSPVPTPAPSMTNGRYHKPRKARPPLPRPLDGEAAKVGAKQGPS
  ESGTEGTAKEAAMKNPSGELKTVTLSKMKQSLGISISGGIESKVQPMVKIEKIFPGGAAF
  LSGALQAGFELVAVDGENLEQVTHQRAVDTIRRAYRNKAREPMELVVRVPGPSPRPSPSD
  SSALTDGGLPADHLPAHQPLDAAPVPAHWLPEPPTNPQTPPTDARLLQPTPSPAPSPALQ
  TPDSKPAPSPRIP
• Function: In cochlear developing hair cells, essential in organizing the USH2 complex at stereocilia ankle links. Blocks inhibition of adenylate cyclase activity mediated by ADGRV1.
• Tissue Specificity: Weakly expressed in the inner ear. Expressed in the retinal pigment epithelium.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hearing loss, autosomal recessive	DIS8G9R9	Definitive	Autosomal recessive	[1]
Usher syndrome type 2D	DISHEVUD	Definitive	GermlineModifyingMutation	[2]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[3]
Deafness	DISKCLH4	Strong	Genetic Variation	[4]
Hearing loss, autosomal recessive 57	DISL21UN	Strong	Autosomal recessive	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Liver cancer	DISDE4BI	Strong	Altered Expression	[3]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[2]
Retinopathy	DISB4B0F	Strong	Biomarker	[6]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Biomarker	[6]
Usher syndrome	DIS9YIS7	Strong	Biomarker	[6]
Usher syndrome type 2	DIS3LO3C	Strong	Biomarker	[7]
Usher syndrome type 2C	DISX2RCU	Limited	Unknown	[2]

1 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 PDZ domain-containing protein 7 (PDZD7).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of PDZ domain-containing protein 7 (PDZD7).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of PDZ domain-containing protein 7 (PDZD7).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of PDZ domain-containing protein 7 (PDZD7).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of PDZ domain-containing protein 7 (PDZD7).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of PDZ domain-containing protein 7 (PDZD7).	[13]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of PDZ domain-containing protein 7 (PDZD7).	[14]

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] PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome. J Clin Invest. 2010 Jun;120(6):1812-23. doi: 10.1172/JCI39715. Epub 2010 May 3.
• [3] Lnc-PDZD7 contributes to stemness properties and chemosensitivity in hepatocellular carcinoma through EZH2-mediated ATOH8 transcriptional repression.J Exp Clin Cancer Res. 2019 Feb 20;38(1):92. doi: 10.1186/s13046-019-1106-2.
• [4] Genetics of Usher Syndrome: New Insights From a Meta-analysis.Otol Neurotol. 2019 Jan;40(1):121-129. doi: 10.1097/MAO.0000000000002054.
• [5] Homozygous disruption of PDZD7 by reciprocal translocation in a consanguineous family: a new member of the Usher syndrome protein interactome causing congenital hearing impairment. Hum Mol Genet. 2009 Feb 15;18(4):655-66. doi: 10.1093/hmg/ddn395. Epub 2008 Nov 20.
• [6] Confirmation of PDZD7 as a Nonsyndromic Hearing Loss Gene.Ear Hear. 2016 Jul-Aug;37(4):e238-46. doi: 10.1097/AUD.0000000000000278.
• [7] Identification of a Potential Founder Effect of a Novel PDZD7 Variant Involved in Moderate-to-Severe Sensorineural Hearing Loss in Koreans.Int J Mol Sci. 2019 Aug 26;20(17):4174. doi: 10.3390/ijms20174174.
• [8] 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.
• [9] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] 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.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.