Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMHRV87)

• DOT Name: FRAS1-related extracellular matrix protein 1 (FREM1)
• Synonyms: Protein QBRICK
• Gene Name: FREM1
• Related Disease:
  Congenital anomaly of kidney and urinary tract
  Oculotrichoanal syndrome
  Renal agenesis
  Renal hypodysplasia/aplasia 1
  Bilateral renal agenesis
  BNAR syndrome
  Cardiovascular disease
  Congenital diaphragmatic hernia
  Fraser syndrome
  HIV infectious disease
  Primary myelofibrosis
  Isolated trigonocephaly
  Renal agenesis, unilateral
  Trigonocephaly 2
  Bifid nose
  Trigonocephaly
• UniProt ID: FREM1_HUMAN
• Pfam ID: PF16184 ; PF03160 ; PF19309 ; PF00059
• Sequence:
  MNSLSWGAANAVLLLLLLAWASPTFISINRGVRVMKGHSAFLSGDDLKFAIPKEKDACKV
  EVVMNEPITQRVGKLTPQVFDCHFLPNEVKYVHNGCPILDEDTVKLRLYRFTERDTFIET
  FILWVYLLEPDCNIIHMSNNVLEVPEFNGLSQAIDKNLLRFDYDRMASLECTVSLDTART
  RLPAHGQMVLGEPRPEEPRGDQPHSFFPESQLRAKLKCPGGSCTPGLKKIGSLKVSCEEF
  LLMGLRYQHLDPPSPNIDYISIQLDLTDTRSKIVYKSESAWLPVYIRAGIPNQIPKAAFM
  AVFILEVDQFILTSLTTSVLDCEEDETPKPLLVFNITKAPLQGYVTHLLDHTRPISSFTW
  KDLSDMQIAYQPPNSSHSERRHDEVELEVYDFFFERSAPMTVHISIRTADTNAPRVSWNT
  GLSLLEGQSRAITWEQFQVVDNDDIGAVRLVTVGGLQHGWLTLRGGKGFLFTVADLQAGV
  VRYHHDDSDSTKDFVVFRIFDGHHSIRHKFPINVLPKDDSPPFLITNVVIELEEGQTILI
  QGSMLRASDVDASDDYIFFNITKPPQAGEIMKKPGPGLIGYPVHGFLQRDLFNGIIYYRH
  FGGEIFEDSFQFVLWDSHEPPNLSVPQVATIHITPVDDQLPKEAPGVSRHLVVKETEVAY
  ITKKQLHFIDSESYDRELVYTITTPPFFSFSHRHLDAGKLFMVDSIPKVVKNPTALELRS
  FTQHAVNYMKVAYMPPMQDIGPHCRDVQFTFSVSNQHGGTLHGICFNITILPVDNQVPEA
  FTNPLKVTEGGQSIISTEHILISDADTKLDNIDLSLRELPLHGRVELNGFPLNSGGTFSW
  GDLHTLKVRYQHDGTEVLQDDLLLEVTDGTNSAEFVLHVEVFPVNDEPPVLKADLMPVMN
  CSEGGEVVITSEYIFATDVDSDNLKLMFVIAREPQHGVVRRAGVTVDQFSQRDVISEAVT
  YKHTGGEIGLMPCFDTITLVVSDGEAGPFVNGCCYNGPNPSVPLHASFPVYDLNITVYPV
  DNQPPSIAIGPVFVVDEGCSTALTVNHLSATDPDTAADDLEFVLVSPPQFGYLENILPSV
  GFEKSNIGISIDSFQWKDMNAFHINYVQSRHLRIEPTADQFTVYVTDGKHHSLEIPFSII
  INPTNDEAPDFVVQNITVCEGQMKELDSSIISAVDLDIPQDALLFSITQKPRHGLLIDRG
  FSKDFSENKQPANPHQKHAPVHSFSMELLKTGMRLTYMHDDSESLADDFTIQLSDGKHKI
  LKTISVEVIPVNDEKPMLSKKAEIAMNMGETRIISSAILSAIDEDSPREKIYYVFERLPQ
  NGQLQLKIGRDWVPLSPGMKCTQEEVDLNLLRYTHTGAMDSQNQDSFTFYLWDGNNRSPA
  LDCQITIKDMEKGDIVILTKPLVVSKGDRGFLTTTTLLAVDGTDKPEELLYVITSPPRYG
  QIEYVHYPGVPITNFSQMDVVGQTVCYVHKSKVTVSSDRFRFIISNGLRTEHGVFEITLE
  TVDRALPVVTRNKGLRLAQGAVGLLSPDLLQLTDPDTPAENLTFLLVQLPQHGQLYLWGT
  GLLQHNFTQQDVDSKNVAYRHSGGDSQTDCFTFMATDGTNQGFIVNGRVWEEPVLFTIQV
  DQLDKTAPRITLLHSPSQVGLLKNGCYGIYITSRVLKASDPDTEDDQIIFKILQGPKHGH
  LENTTTGEFIHEKFSQKDLNSKTILYIINPSLEVNSDTVEFQIMDPTGNSATPQILELKW
  SHIEWSQTEYEVCENVGLLPLEIIRRGYSMDSAFVGIKVNQVSAAVGKDFTVIPSKLIQF
  DPGMSTKMWNIAITYDGLEEDDEVFEVILNSPVNAVLGTKTKAAVKILDSKGGQCHPSYS
  SNQSKHSTWEKGIWHLLPPGSSSSTTSGSFHLERRPLPSSMQLAVIRGDTLRGFDSTDLS
  QRKLRTRGNGKTVRPSSVYRNGTDIIYNYHGIVSLKLEDDSFPTHKRKAKVSIISQPQKT
  IKVAELPQADKVESTTDSHFPRQDQLPSFPKNCTLELKGLFHFEEGIQKLYQCNGIAWKA
  WSPQTKDVEDKSCPAGWHQHSGYCHILITEQKGTWNAAAQACREQYLGNLVTVFSRQHMR
  WLWDIGGRKSFWIGLNDQVHAGHWEWIGGEPVAFTNGRRGPSQRSKLGKSCVLVQRQGKW
  QTKDCRRAKPHNYVCSRKL
• Function: Extracellular matrix protein that plays a role in epidermal differentiation and is required for epidermal adhesion during embryonic development.
• KEGG Pathway: ECM-receptor interaction (hsa04512)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital anomaly of kidney and urinary tract	DIS84IVH	Definitive	Genetic Variation	[1]
Oculotrichoanal syndrome	DIS5GWU7	Definitive	Autosomal recessive	[2]
Renal agenesis	DIS0M9AF	Definitive	Biomarker	[3]
Renal hypodysplasia/aplasia 1	DISOH8XN	Definitive	Biomarker	[3]
Bilateral renal agenesis	DISOR5IA	Strong	Biomarker	[4]
BNAR syndrome	DIS2I9RV	Strong	Autosomal recessive	[5]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[6]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Genetic Variation	[7]
Fraser syndrome	DISCLC2B	Strong	Genetic Variation	[8]
HIV infectious disease	DISO97HC	Strong	Genetic Variation	[9]
Primary myelofibrosis	DIS6L0CN	Strong	Biomarker	[10]
Isolated trigonocephaly	DISIEY3W	Supportive	Autosomal dominant	[11]
Renal agenesis, unilateral	DIS53ZJ8	Supportive	Autosomal dominant	[12]
Trigonocephaly 2	DISHHYIP	Disputed	Autosomal dominant	[11]
Bifid nose	DISOZ09B	Limited	Genetic Variation	[13]
Trigonocephaly	DISHV6BA	Limited	GermlineCausalMutation	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of FRAS1-related extracellular matrix protein 1 (FREM1).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of FRAS1-related extracellular matrix protein 1 (FREM1).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of FRAS1-related extracellular matrix protein 1 (FREM1).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of FRAS1-related extracellular matrix protein 1 (FREM1).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of FRAS1-related extracellular matrix protein 1 (FREM1).	[18]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of FRAS1-related extracellular matrix protein 1 (FREM1).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of FRAS1-related extracellular matrix protein 1 (FREM1).	[20]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of FRAS1-related extracellular matrix protein 1 (FREM1).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of FRAS1-related extracellular matrix protein 1 (FREM1).	[21]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of FRAS1-related extracellular matrix protein 1 (FREM1).	[22]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of FRAS1-related extracellular matrix protein 1 (FREM1).	[24]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of FRAS1-related extracellular matrix protein 1 (FREM1).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of FRAS1-related extracellular matrix protein 1 (FREM1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of FRAS1-related extracellular matrix protein 1 (FREM1).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of FRAS1-related extracellular matrix protein 1 (FREM1).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of FRAS1-related extracellular matrix protein 1 (FREM1).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of FRAS1-related extracellular matrix protein 1 (FREM1).	[26]

References

• [1] Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract.J Am Soc Nephrol. 2014 Sep;25(9):1917-22. doi: 10.1681/ASN.2013101103. Epub 2014 Apr 3.
• [2] Manitoba Oculotrichoanal (MOTA) syndrome: report of eight new cases. Am J Med Genet A. 2007 Apr 15;143A(8):853-7. doi: 10.1002/ajmg.a.31446.
• [3] The role of Fras1/Frem proteins in the structure and function of basement membrane.Int J Biochem Cell Biol. 2011 Apr;43(4):487-95. doi: 10.1016/j.biocel.2010.12.016. Epub 2010 Dec 21.
• [4] Deficiency of FRAS1-related extracellular matrix 1 (FREM1) causes congenital diaphragmatic hernia in humans and mice.Hum Mol Genet. 2013 Mar 1;22(5):1026-38. doi: 10.1093/hmg/dds507. Epub 2012 Dec 5.
• [5] FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome. Am J Hum Genet. 2009 Sep;85(3):414-8. doi: 10.1016/j.ajhg.2009.08.010.
• [6] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [7] The role of FREM2 and FRAS1 in the development of congenital diaphragmatic hernia.Hum Mol Genet. 2018 Jun 15;27(12):2064-2075. doi: 10.1093/hmg/ddy110.
• [8] A homozygous mutation p.Arg2167Trp in FREM2 causes isolated cryptophthalmos.Hum Mol Genet. 2018 Jul 1;27(13):2357-2366. doi: 10.1093/hmg/ddy144.
• [9] A genetic polymorphism of FREM1 is associated with resistance against HIV infection in the Pumwani sex worker cohort.J Virol. 2012 Nov;86(21):11899-905. doi: 10.1128/JVI.01499-12. Epub 2012 Aug 22.
• [10] Shared and Tissue-Specific Expression Signatures between Bone Marrow from Primary Myelofibrosis and Essential Thrombocythemia.Exp Hematol. 2019 Nov;79:16-25.e3. doi: 10.1016/j.exphem.2019.10.001. Epub 2019 Nov 1.
• [11] Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice. PLoS Genet. 2011 Sep;7(9):e1002278. doi: 10.1371/journal.pgen.1002278. Epub 2011 Sep 8.
• [12] Clinical implications of the solitary functioning kidney. Clin J Am Soc Nephrol. 2014 May;9(5):978-86. doi: 10.2215/CJN.08900813. Epub 2013 Dec 26.
• [13] Novel FREM1 mutations expand the phenotypic spectrum associated with Manitoba-oculo-tricho-anal (MOTA) syndrome and bifid nose renal agenesis anorectal malformations (BNAR) syndrome.Am J Med Genet A. 2013 Mar;161A(3):473-8. doi: 10.1002/ajmg.a.35736. Epub 2013 Feb 8.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [20] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [21] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [22] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [23] 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.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [29] 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.