Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT14JQT8)

• DOT Name: T-box brain protein 1 (TBR1)
• Synonyms: T-brain-1; TBR-1; TES-56
• Gene Name: TBR1
• Related Disease:
  Autism
  Complex neurodevelopmental disorder
  Neurodevelopmental disorder
  Schizophrenia
  Trypanosomiasis
  Occipital pachygyria and polymicrogyria
  Autism spectrum disorder
  Intellectual disability
  Pervasive developmental disorder
• UniProt ID: TBR1_HUMAN
• Pfam ID: PF00907 ; PF16176
• Sequence:
  MQLEHCLSPSIMLSKKFLNVSSSYPHSGGSELVLHDHPIISTTDNLERSSPLKKITRGMT
  NQSDTDNFPDSKDSPGDVQRSKLSPVLDGVSELRHSFDGSAADRYLLSQSSQPQSAATAP
  SAMFPYPGQHGPAHPAFSIGSPSRYMAHHPVITNGAYNSLLSNSSPQGYPTAGYPYPQQY
  GHSYQGAPFYQFSSTQPGLVPGKAQVYLCNRPLWLKFHRHQTEMIITKQGRRMFPFLSFN
  ISGLDPTAHYNIFVDVILADPNHWRFQGGKWVPCGKADTNVQGNRVYMHPDSPNTGAHWM
  RQEISFGKLKLTNNKGASNNNGQMVVLQSLHKYQPRLHVVEVNEDGTEDTSQPGRVQTFT
  FPETQFIAVTAYQNTDITQLKIDHNPFAKGFRDNYDTIYTGCDMDRLTPSPNDSPRSQIV
  PGARYAMAGSFLQDQFVSNYAKARFHPGAGAGPGPGTDRSVPHTNGLLSPQQAEDPGAPS
  PQRWFVTPANNRLDFAASAYDTATDFAGNAATLLSYAAAGVKALPLQAAGCTGRPLGYYA
  DPSGWGARSPPQYCGTKSGSVLPCWPNSAAAAARMAGANPYLGEEAEGLAAERSPLPPGA
  AEDAKPKDLSDSSWIETPSSIKSIDSSDSGIYEQAKRRRISPADTPVSESSSPLKSEVLA
  QRDCEKNCAKDISGYYGFYSHS
• Function: Transcriptional repressor involved in multiple aspects of cortical development, including neuronal migration, laminar and areal identity, and axonal projection. As transcriptional repressor of FEZF2, it blocks the formation of the corticospinal (CS) tract from layer 6 projection neurons, thereby restricting the origin of CS axons specifically to layer 5 neurons.
• Tissue Specificity: Brain.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Definitive	Autosomal dominant	[1]
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[2]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[3]
Schizophrenia	DISSRV2N	Strong	Biomarker	[4]
Trypanosomiasis	DISUBO83	Strong	Biomarker	[5]
Occipital pachygyria and polymicrogyria	DISIAYWB	Supportive	Autosomal recessive	[6]
Autism spectrum disorder	DISXK8NV	Limited	Biomarker	[7]
Intellectual disability	DISMBNXP	Limited	Biomarker	[6]
Pervasive developmental disorder	DIS51975	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of T-box brain protein 1 (TBR1).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of T-box brain protein 1 (TBR1).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of T-box brain protein 1 (TBR1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of T-box brain protein 1 (TBR1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of T-box brain protein 1 (TBR1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of T-box brain protein 1 (TBR1).	[14]

References

• [1] De novo TBR1 mutations in sporadic autism disrupt protein functions. Nat Commun. 2014 Sep 18;5:4954. doi: 10.1038/ncomms5954.
• [2] 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.
• [3] Functional characterization of TBR1 variants in neurodevelopmental disorder.Sci Rep. 2018 Sep 24;8(1):14279. doi: 10.1038/s41598-018-32053-6.
• [4] Cerebral organoids reveal early cortical maldevelopment in schizophrenia-computational anatomy and genomics, role of FGFR1.Transl Psychiatry. 2017 Nov 17;7(11):6. doi: 10.1038/s41398-017-0054-x.
• [5] Unraveling cryptic epizootiology of equid trypanosomosis in Punjab state of India by parasitological and sero-molecular techniques.Acta Trop. 2018 Sep;185:18-26. doi: 10.1016/j.actatropica.2018.04.018. Epub 2018 Apr 23.
• [6] Mutations in TBR1 gene leads to cortical malformations and intellectual disability. Eur J Med Genet. 2018 Dec;61(12):759-764. doi: 10.1016/j.ejmg.2018.09.012. Epub 2018 Sep 27.
• [7] Haploinsufficiency of autism causative gene Tbr1 impairs olfactory discrimination and neuronal activation of the olfactory system in mice.Mol Autism. 2019 Feb 11;10:5. doi: 10.1186/s13229-019-0257-5. eCollection 2019.
• [8] A TBR1-K228E Mutation Induces Tbr1 Upregulation, Altered Cortical Distribution of Interneurons, Increased Inhibitory Synaptic Transmission, and Autistic-Like Behavioral Deficits in Mice.Front Mol Neurosci. 2019 Oct 9;12:241. doi: 10.3389/fnmol.2019.00241. eCollection 2019.
• [9] Effect of all-trans retinoic acid on sodium/iodide symporter expression, radioiodine uptake and gene expression profiles in a human anaplastic thyroid carcinoma cell line. Nucl Med Biol. 2006 Oct;33(7):875-82. doi: 10.1016/j.nucmedbio.2006.07.004.
• [10] 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.
• [11] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [12] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [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.
• [14] 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.