Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3BM9B0)

• DOT Name: Bromodomain and WD repeat-containing protein 3 (BRWD3)
• Gene Name: BRWD3
• Related Disease:
  Intellectual disability, X-linked 93
  Partington syndrome
  X-linked syndromic intellectual disability
  Cleft palate
  Intellectual disability
  Isolated cleft palate
  Megalencephaly
  Obesity
  X-linked intellectual disability
  Breast cancer
  Breast carcinoma
  Childhood epilepsy with centrotemporal spikes
  West syndrome
• UniProt ID: BRWD3_HUMAN
• Pfam ID: PF00439 ; PF00400
• Sequence:
  MAAAPTQIEAELYYLIARFLQSGPCNKSAQVLVQELEEHQLIPRRLDWEGKEHRRSFEDL
  VAANAHIPPDYLLKICERIGPLLDKEIPQSVPGVQTLLGVGRQSLLRDAKDCKSTLWNGS
  AFAALHRGRPPELPVNYVKPPNVVNITSARQLTGCSRFGHIFPSSAYQHIKMHKRILGHL
  SSVYCVAFDRSGRRIFTGSDDCLVKIWATDDGRLLATLRGHSAEISDMAVNYENTLIAAG
  SCDKVVRVWCLRTCAPVAVLQGHSASITSIQFCPSTKGTNRYLTSTGADGTICFWQWHVK
  TMKFRDRPVKFTERSRPGVQISCSSFSSGGMFITTGSTDHVIRIYYLGSEVPEKIAELES
  HTDKVVAVQFCNNGDSLRFVSGSRDGTARIWQYQQQEWKSIVLDMATKMTGNNLPSGEDK
  ITKLKVTMVAWDRYDTTVITAVNNFLLKVWNSITGQLLHTLSGHDDEVFVLEAHPFDQRI
  ILSAGHDGNIFIWDLDRGTKIRNYFNMIEGQGHGAVFDCKFSPDGNHFACTDSHGHLLLF
  GFGCSKYYEKIPDQMFFHTDYRPLIRDANNYVLDEQTQQAPHLMPPPFLVDVDGNPHPTK
  FQRLVPGRENCKDEQLIPQLGYVANGDGEVVEQVIGQQTNDQDESILDGIIRELQREQDL
  RLINEGDVPHLPVNRAYSVNGALRSPNMDISSSPNIRLRRHSSQIEGVRQMHNNAPRSQM
  ATERDLMAWSRRVVVNELNNGVSRVQEECRTAKGDIEISLYTVEKKKKPSYTTQRNDYEP
  SCGRSLRRTQRKRQHTYQTRSNIEHNSQASCQNSGVQEDSDSSSEEDETVGTSDASVEDP
  VVEWQSESSSSDSSSEYSDWTADAGINLQPPKRQTRQTTRKICSSSDEENLKSLEERQKK
  PKQTRKKKGGLVSIAGEPNEEWFAPQWILDTIPRRSPFVPQMGDELIYFRQGHEAYVRAV
  RKSKIYSVNLQKQPWNKMDLREQEFVKIVGIKYEVGPPTLCCLKLAFLDPISGKMTGESF
  SIKYHDMPDVIDFLVLHQFYNEAKERNWQIGDRFRSIIDDAWWFGTVESQQPFQPEYPDS
  SFQCYSVHWDNNEREKMSPWDMEPIPEGTAFPDEVGAGVPVSQEELTALLYKPQEGEWGA
  HSRDEECERVIQGINHLLSLDFASPFAVPVDLSAYPLYCTVVAYPTDLNTIRRRLENRFY
  RRISALMWEVRYIEHNARTFNEPDSPIVKAAKIVTDVLLRFIGDQSCTDILDTYNKIKAE
  ERNSTDAEEDTEIVDLDSDGPGTSSGRKVKCRGRRQSLKCNPDAWKKQCKELLSLIYERE
  DSEPFRQPADLLSYPGHQEQEGESSESVVPERQQDSSLSEDYQDVIDTPVDFSTVKETLE
  AGNYGSPLEFYKDVRQIFNNSKAYTSNKKSRIYSMMLRLSALFESHIKNIISEYKSAIQS
  QKRRRPRYRKRLRSSSSSLSSSGAPSPKGKQKQMKLQPKNDQNTSVSHARTSSPFSSPVS
  DAAEGLSLYLLDDEPDGPFSSSSFGGYSRSGNSHDPGKAKSFRNRVLPVKQDHSLDGPLT
  NGDGREPRTGIKRKLLSASEEDENMGGEDKEKKETKEKSHLSTSESGELGSSLSSESTCG
  SDSDSESTSRTDQDYVDGDHDYSKFIQTRPKRKLRKQHGNGKRNWKTRGTGGRGRWGRWG
  RWSRGGRGRGGRGRGSRGRGGGGTRGRGRGRGGRGASRGATRAKRARIADDEFDTMFSGR
  FSRLPRIKTRNQGRRTVLYNDDSDNDNFVSTEDPLNLGTSRSGRVRKMTEKARVSHLMGW
  NY
• Function: Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape.
• Tissue Specificity: Found in most adult tissues. Down-regulated in a majority of the B-CLL cases examined.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, X-linked 93	DIS5EFCO	Definitive	X-linked recessive	[1]
Partington syndrome	DIS3H205	Definitive	Biomarker	[2]
X-linked syndromic intellectual disability	DISG1YOH	Definitive	X-linked	[3]
Cleft palate	DIS6G5TF	Strong	Genetic Variation	[4]
Intellectual disability	DISMBNXP	Strong	Biomarker	[5]
Isolated cleft palate	DISV80CD	Strong	Genetic Variation	[4]
Megalencephaly	DISYW5SV	Strong	Biomarker	[5]
Obesity	DIS47Y1K	Strong	Biomarker	[5]
X-linked intellectual disability	DISYJBY3	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[6]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[6]
Childhood epilepsy with centrotemporal spikes	DISKT2L5	Limited	Autosomal dominant	[7]
West syndrome	DISLIAU9	Limited	Autosomal dominant	[7]

5 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 Bromodomain and WD repeat-containing protein 3 (BRWD3).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Bromodomain and WD repeat-containing protein 3 (BRWD3).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Bromodomain and WD repeat-containing protein 3 (BRWD3).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Bromodomain and WD repeat-containing protein 3 (BRWD3).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Bromodomain and WD repeat-containing protein 3 (BRWD3).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Bromodomain and WD repeat-containing protein 3 (BRWD3).	[13]

References

• [1] Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly. Am J Hum Genet. 2007 Aug;81(2):367-74. doi: 10.1086/520677. Epub 2007 Jun 26.
• [2] Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability.Am J Hum Genet. 2017 May 4;100(5):725-736. doi: 10.1016/j.ajhg.2017.03.010.
• [3] 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.
• [4] A 5.8 Mb interstitial deletion on chromosome Xq21.1 in a boy with intellectual disability, cleft palate, hearing impairment and combined growth hormone deficiency.BMC Med Genet. 2015 Sep 1;16:74. doi: 10.1186/s12881-015-0220-z.
• [5] Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients.Am J Med Genet C Semin Med Genet. 2019 Dec;181(4):638-643. doi: 10.1002/ajmg.c.31750. Epub 2019 Nov 12.
• [6] Comparative profiling of plasma proteome from breast cancer patients reveals thrombospondin-1 and BRWD3 as serological biomarkers.Exp Mol Med. 2012 Jan 31;44(1):36-44. doi: 10.3858/emm.2012.44.1.003.
• [7] 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.
• [8] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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.