Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW1Q8RM)

• DOT Name: T-box transcription factor TBX6 (TBX6)
• Synonyms: T-box protein 6
• Gene Name: TBX6
• Related Disease:
  Atrioventricular block
  Spondylocostal dysostosis
  Spondylocostal dysostosis 2, autosomal recessive
  Spondylocostal dysostosis 3, autosomal recessive
  Spondylocostal dysostosis 4, autosomal recessive
  Spondylocostal dysostosis 5
  Autosomal dominant spondylocostal dysostosis
  Congenital anomaly of kidney and urinary tract
  Sickle-cell anaemia
  Systemic primary carnitine deficiency disease
• UniProt ID: TBX6_HUMAN
• Pfam ID: PF00907
• Sequence:
  MYHPRELYPSLGAGYRLGPAQPGADSSFPPALAEGYRYPELDTPKLDCFLSGMEAAPRTL
  AAHPPLPLLPPAMGTEPAPSAPEALHSLPGVSLSLENRELWKEFSSVGTEMIITKAGRRM
  FPACRVSVTGLDPEARYLFLLDVIPVDGARYRWQGRRWEPSGKAEPRLPDRVYIHPDSPA
  TGAHWMRQPVSFHRVKLTNSTLDPHGHLILHSMHKYQPRIHLVRAAQLCSQHWGGMASFR
  FPETTFISVTAYQNPQITQLKIAANPFAKGFRENGRNCKRERDARVKRKLRGPEPAATEA
  YGSGDTPGGPCDSTLGGDIRESDPEQAPAPGEATAAPAPLCGGPSAEAYLLHPAAFHGAP
  SHLPTRSPSFPEAPDSGRSAPYSAAFLELPHGSGGSGYPAAPPAVPFAPHFLQGGPFPLP
  YTAPGGYLDVGSKPMY
• Function: T-box transcription factor that plays an essential role in the determination of the fate of axial stem cells: neural vs mesodermal. Acts in part by down-regulating, a specific enhancer (N1) of SOX2, to inhibit neural development. Seems to play also an essential role in left/right axis determination and acts through effects on Notch signaling around the node as well as through an effect on the morphology and motility of the nodal cilia.
• Tissue Specificity: Expressed in fetal tail bud, posterior spinal tissue, intervertebral disk and testis. Also expressed in adult testis, kidney, lung, muscle and thymus.
• Reactome Pathway:
  Somitogenesis (R-HSA-9824272)
  Formation of the posterior neural plate (R-HSA-9832991)
  Formation of paraxial mesoderm (R-HSA-9793380)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrioventricular block	DIS8YLE6	Strong	Biomarker	[1]
Spondylocostal dysostosis	DISTPWFK	Strong	Genetic Variation	[2]
Spondylocostal dysostosis 2, autosomal recessive	DISR3NXE	Strong	Biomarker	[3]
Spondylocostal dysostosis 3, autosomal recessive	DIS10LTO	Strong	Biomarker	[3]
Spondylocostal dysostosis 4, autosomal recessive	DIS3HQRC	Strong	Biomarker	[3]
Spondylocostal dysostosis 5	DISOB4HV	Moderate	Semidominant	[4]
Autosomal dominant spondylocostal dysostosis	DIS7OT0S	Supportive	Autosomal dominant	[5]
Congenital anomaly of kidney and urinary tract	DIS84IVH	Limited	Autosomal dominant	[4]
Sickle-cell anaemia	DIS5YNZB	Limited	Biomarker	[6]
Systemic primary carnitine deficiency disease	DIS9OPZ4	Limited	Biomarker	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	T-box transcription factor TBX6 (TBX6) decreases the response to substance of Arsenic trioxide.	[14]

9 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 T-box transcription factor TBX6 (TBX6).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of T-box transcription factor TBX6 (TBX6).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of T-box transcription factor TBX6 (TBX6).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone affects the expression of T-box transcription factor TBX6 (TBX6).	[7]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of T-box transcription factor TBX6 (TBX6).	[7]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of T-box transcription factor TBX6 (TBX6).	[9]
Dolutegravir	DMCZGRE	Approved	Dolutegravir increases the expression of T-box transcription factor TBX6 (TBX6).	[10]
CHIR-99021	DMB8MNU	Patented	CHIR-99021 increases the expression of T-box transcription factor TBX6 (TBX6).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of T-box transcription factor TBX6 (TBX6).	[13]

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 affects the methylation of T-box transcription factor TBX6 (TBX6).	[11]

References

• [1] Arrhythmias and conduction disorders associated with atrial septal defects.J Thorac Dis. 2018 Sep;10(Suppl 24):S2940-S2944. doi: 10.21037/jtd.2018.08.27.
• [2] Autosomal recessive variations of TBX6, from congenital scoliosis to spondylocostal dysostosis.Clin Genet. 2017 Jun;91(6):908-912. doi: 10.1111/cge.12918. Epub 2017 Feb 22.
• [3] Development of rib-vertebrae: a new mutation in the house mouse with accessory caudal duplications.Anat Embryol (Berl). 1985;173(1):111-6. doi: 10.1007/BF00707309.
• [4] 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.
• [5] Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6. Hum Mol Genet. 2013 Apr 15;22(8):1625-31. doi: 10.1093/hmg/ddt012. Epub 2013 Jan 17.
• [6] Bi-allelic loss of function variants of TBX6 causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis.J Med Genet. 2019 Sep;56(9):622-628. doi: 10.1136/jmedgenet-2018-105920. Epub 2019 Apr 22.
• [7] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [8] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [9] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [10] Dolutegravir Impairs Stem Cell-Based 3D Morphogenesis Models in a Manner Dependent on Dose and Timing of Exposure: An Implication for Its Developmental Toxicity. Toxicol Sci. 2021 Nov 24;184(2):191-203. doi: 10.1093/toxsci/kfab112.
• [11] 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.
• [12] Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells. Reprod Toxicol. 2020 Jan;91:74-91. doi: 10.1016/j.reprotox.2019.10.004. Epub 2019 Nov 8.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.