Details of Drug Off-Target (DOT)

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

• DOT Name: Protein disulfide isomerase CRELD1 (CRELD1)
• Synonyms: EC 5.3.4.1; Cysteine-rich with EGF-like domain protein 1
• Gene Name: CRELD1
• Related Disease:
  Atrioventricular septal defect, susceptibility to, 2
  Ventricular septal defect
  Visceral heterotaxy
  Congenital heart disease
  Heart septal defect
• UniProt ID: CREL1_HUMAN
• EC Number: 5.3.4.1
• Pfam ID: PF11938 ; PF07645
• Sequence:
  MAPWPPKGLVPAMLWGLSLFLNLPGPIWLQPSPPPQSSPPPQPHPCHTCRGLVDSFNKGL
  ERTIRDNFGGGNTAWEEENLSKYKDSETRLVEVLEGVCSKSDFECHRLLELSEELVESWW
  FHKQQEAPDLFQWLCSDSLKLCCPAGTFGPSCLPCPGGTERPCGGYGQCEGEGTRGGSGH
  CDCQAGYGGEACGQCGLGYFEAERNASHLVCSACFGPCARCSGPEESNCLQCKKGWALHH
  LKCVDIDECGTEGANCGADQFCVNTEGSYECRDCAKACLGCMGAGPGRCKKCSPGYQQVG
  SKCLDVDECETEVCPGENKQCENTEGGYRCICAEGYKQMEGICVKEQIPESAGFFSEMTE
  DELVVLQQMFFGIIICALATLAAKGDLVFTAIFIGAVAAMTGYWLSERSDRVLEGFIKGR
• Function: Protein disulfide isomerase. Promotes the localization of acetylcholine receptors (AChRs) to the plasma membrane.
• Tissue Specificity: Highly expressed in fetal lung, liver, kidney, adult heart, brain and skeletal muscle. Weakly expressed in placenta, fetal brain, and adult lung, liver, kidney and pancreas.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrioventricular septal defect, susceptibility to, 2	DISH59M7	Strong	Autosomal dominant	[1]
Ventricular septal defect	DISICO41	Strong	Genetic Variation	[2]
Visceral heterotaxy	DIS1DV90	moderate	Genetic Variation	[3]
Congenital heart disease	DISQBA23	Limited	Autosomal dominant	[4]
Heart septal defect	DISQ5C5J	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein disulfide isomerase CRELD1 (CRELD1).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein disulfide isomerase CRELD1 (CRELD1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein disulfide isomerase CRELD1 (CRELD1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Protein disulfide isomerase CRELD1 (CRELD1).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Protein disulfide isomerase CRELD1 (CRELD1).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Protein disulfide isomerase CRELD1 (CRELD1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein disulfide isomerase CRELD1 (CRELD1).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Protein disulfide isomerase CRELD1 (CRELD1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein disulfide isomerase CRELD1 (CRELD1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein disulfide isomerase CRELD1 (CRELD1).	[16]

2 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 Protein disulfide isomerase CRELD1 (CRELD1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein disulfide isomerase CRELD1 (CRELD1).	[12]

References

• [1] 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.
• [2] Germline mutations in NKX2-5, GATA4, and CRELD1 are rare in a Mexican sample of Down syndrome patients with endocardial cushion and septal heart defects.Pediatr Cardiol. 2015 Apr;36(4):802-8. doi: 10.1007/s00246-014-1091-3. Epub 2014 Dec 19.
• [3] Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects. Am J Hum Genet. 2003 Apr;72(4):1047-52. doi: 10.1086/374319. Epub 2003 Mar 11.
• [4] 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.
• [5] Analysis of gene copy number variations in patients with congenital heart disease using multiplex ligation-dependent probe amplification.Anatol J Cardiol. 2018 Jul;20(1):9-15. doi: 10.14744/AnatolJCardiol.2018.70481.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [8] 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.
• [9] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [10] 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.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] 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.
• [13] 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.
• [14] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [15] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [16] 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.