Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT33GO6E)

• DOT Name: Protein Shroom4 (SHROOM4)
• Synonyms: Second homolog of apical protein
• Gene Name: SHROOM4
• Related Disease:
  Cognitive impairment
  Dent disease
  Epilepsy
  B-cell neoplasm
  Breast cancer
  Colitis
  Neurodevelopmental disorder
  Trichohepatoenteric syndrome
  X-linked intellectual disability
  Intellectual disability
  X-linked intellectual disability, Stocco dos Santos type
  X-linked complex neurodevelopmental disorder
• UniProt ID: SHRM4_HUMAN
• PDB ID: 2EDP
• Pfam ID: PF08687 ; PF00595
• Sequence:
  MENRPGSFQYVPVQLQGGAPWGFTLKGGLEHCEPLTVSKIEDGGKAALSQKMRTGDELVN
  INGTPLYGSRQEALILIKGSFRILKLIVRRRNAPVSRPHSWHVAKLLEGCPEAATTMHFP
  SEAFSLSWHSGCNTSDVCVQWCPLSRHCSTEKSSSIGSMESLEQPGQATYESHLLPIDQN
  MYPNQRDSAYSSFSASSNASDCALSLRPEEPASTDCIMQGPGPTKAPSGRPNVAETSGGS
  RRTNGGHLTPSSQMSSRPQEGYQSGPAKAVRGPPQPPVRRDSLQASRAQLLNGEQRRASE
  PVVPLPQKEKLSLEPVLPARNPNRFCCLSGHDQVTSEGHQNCEFSQPPESSQQGSEHLLM
  QASTKAVGSPKACDRASSVDSNPLNEASAELAKASFGRPPHLIGPTGHRHSAPEQLLASH
  LQHVHLDTRGSKGMELPPVQDGHQWTLSPLHSSHKGKKSPCPPTGGTHDQSSKERKTRQV
  DDRSLVLGHQSQSSPPHGEADGHPSEKGFLDPNRTSRAASELANQQPSASGSLVQQATDC
  SSTTKAASGTEAGEEGDSEPKECSRMGGRRSGGTRGRSIQNRRKSERFATNLRNEIQRRK
  AQLQKSKGPLSQLCDTKEPVEETQEPPESPPLTASNTSLLSSCKKPPSPRDKLFNKSMML
  RARSSECLSQAPESHESRTGLEGRISPGQRPGQSSLGLNTWWKAPDPSSSDPEKAHAHCG
  VRGGHWRWSPEHNSQPLVAAAMEGPSNPGDNKELKASTAQAGEDAILLPFADRRKFFEES
  SKSLSTSHLPGLTTHSNKTFTQRPKPIDQNFQPMSSSCRELRRHPMDQSYHSADQPYHAT
  DQSYHSMSPLQSETPTYSECFASKGLENSMCCKPLHCGDFDYHRTCSYSCSVQGALVHDP
  CIYCSGEICPALLKRNMMPNCYNCRCHHHQCIRCSVCYHNPQHSALEDSSLAPGNTWKPR
  KLTVQEFPGDKWNPITGNRKTSQSGREMAHSKTSFSWATPFHPCLENPALDLSSYRAISS
  LDLLGDFKHALKKSEETSVYEEGSSLASMPHPLRSRAFSESHISLAPQSTRAWGQHRREL
  FSKGDETQSDLLGARKKAFPPPRPPPPNWEKYRLFRAAQQQKQQQQQQKQQEEEEEEEEE
  EEEEEEEEEEEAEEEEEELPPQYFSSETSGSCALNPEEVLEQPQPLSFGHLEGSRQGSQS
  VPAEQESFALHSSDFLPPIRGHLGSQPEQAQPPCYYGIGGLWRTSGQEATESAKQEFQHF
  SPPSGAPGIPTSYSAYYNISVAKAELLNKLKDQPEMAEIGLGEEEVDHELAQKKIQLIES
  ISRKLSVLREAQRGLLEDINANSALGEEVEANLKAVCKSNEFEKYHLFVGDLDKVVNLLL
  SLSGRLARVENALNSIDSEANQEKLVLIEKKQQLTGQLADAKELKEHVDRREKLVFGMVS
  RYLPQDQLQDYQHFVKMKSALIIEQRELEEKIKLGEEQLKCLRESLLLGPSNF
• Function: Probable regulator of cytoskeletal architecture that plays an important role in development. May regulate cellular and cytoskeletal architecture by modulating the spatial distribution of myosin II.
• Tissue Specificity: Expressed in all fetal and adult tissues investigated. Expressed in adult heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. In brain regions detected in cerebellum, cerebral cortex, medulla, spinal cord, occipital pole, frontal lobe, temporal lobe and putamen. The expression is strongest in the medulla and weakest in the cerebral cortex.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cognitive impairment	DISH2ERD	Definitive	Biomarker	[1]
Dent disease	DISRDLFN	Definitive	Genetic Variation	[2]
Epilepsy	DISBB28L	Definitive	Biomarker	[1]
B-cell neoplasm	DISVY326	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[4]
Colitis	DISAF7DD	Strong	Biomarker	[5]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[6]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[7]
X-linked intellectual disability	DISYJBY3	Strong	Genetic Variation	[8]
Intellectual disability	DISMBNXP	moderate	Biomarker	[2]
X-linked intellectual disability, Stocco dos Santos type	DISV1VZF	Supportive	X-linked	[8]
X-linked complex neurodevelopmental disorder	DISI3QE9	Disputed	X-linked	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Protein Shroom4 (SHROOM4).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein Shroom4 (SHROOM4).	[15]

5 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 Protein Shroom4 (SHROOM4).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein Shroom4 (SHROOM4).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein Shroom4 (SHROOM4).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein Shroom4 (SHROOM4).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein Shroom4 (SHROOM4).	[16]

References

• [1] Epilepsy and intellectual disability linked protein Shrm4 interaction with GABA(B)Rs shapes inhibitory neurotransmission.Nat Commun. 2017 Mar 6;8:14536. doi: 10.1038/ncomms14536.
• [2] Familial Xp11.22 microdeletion including SHROOM4 and CLCN5 is associated with intellectual disability, short stature, microcephaly and Dent disease: a case report.BMC Med Genomics. 2019 Jan 10;12(1):6. doi: 10.1186/s12920-018-0471-6.
• [3] Overexpression of Shrm4 promotes proliferation and differentiation of neural stem cells through activation of GABA signaling pathway.Mol Cell Biochem. 2020 Jan;463(1-2):115-126. doi: 10.1007/s11010-019-03634-4. Epub 2019 Oct 25.
• [4] A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population.Nat Genet. 2010 Oct;42(10):885-92. doi: 10.1038/ng.669. Epub 2010 Sep 19.
• [5] Serum-Derived Hyaluronan-Associated Protein Is a Novel Biomarker for Inflammatory Bowel Diseases.Digestion. 2017;95(2):146-155. doi: 10.1159/000456071. Epub 2017 Feb 4.
• [6] Identification of novel genetic causes of Rett syndrome-like phenotypes. J Med Genet. 2016 Mar;53(3):190-9. doi: 10.1136/jmedgenet-2015-103568. Epub 2016 Jan 6.
• [7] Phenotype-genotype correlations in 17 new patients with an Xp11.23p11.22 microduplication and review of the literature.Am J Med Genet A. 2015 Jan;167A(1):111-22. doi: 10.1002/ajmg.a.36807. Epub 2014 Nov 25.
• [8] Disruptions of the novel KIAA1202 gene are associated with X-linked mental retardation. Hum Genet. 2006 Jan;118(5):578-90. doi: 10.1007/s00439-005-0072-2. Epub 2005 Oct 26.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] 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.