Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLNWI5G)

• DOT Name: SLIT and NTRK-like protein 6 (SLITRK6)
• Gene Name: SLITRK6
• Related Disease:
  High myopia-sensorineural deafness syndrome
  Hearing loss, autosomal recessive
• UniProt ID: SLIK6_HUMAN
• Pfam ID: PF13855
• Sequence:
  MKLWIHLFYSSLLACISLHSQTPVLSSRGSCDSLCNCEEKDGTMLINCEAKGIKMVSEIS
  VPPSRPFQLSLLNNGLTMLHTNDFSGLTNAISIHLGFNNIADIEIGAFNGLGLLKQLHIN
  HNSLEILKEDTFHGLENLEFLQADNNFITVIEPSAFSKLNRLKVLILNDNAIESLPPNIF
  RFVPLTHLDLRGNQLQTLPYVGFLEHIGRILDLQLEDNKWACNCDLLQLKTWLENMPPQS
  IIGDVVCNSPPFFKGSILSRLKKESICPTPPVYEEHEDPSGSLHLAATSSINDSRMSTKT
  TSILKLPTKAPGLIPYITKPSTQLPGPYCPIPCNCKVLSPSGLLIHCQERNIESLSDLRP
  PPQNPRKLILAGNIIHSLMKSDLVEYFTLEMLHLGNNRIEVLEEGSFMNLTRLQKLYLNG
  NHLTKLSKGMFLGLHNLEYLYLEYNAIKEILPGTFNPMPKLKVLYLNNNLLQVLPPHIFS
  GVPLTKVNLKTNQFTHLPVSNILDDLDLLTQIDLEDNPWDCSCDLVGLQQWIQKLSKNTV
  TDDILCTSPGHLDKKELKALNSEILCPGLVNNPSMPTQTSYLMVTTPATTTNTADTILRS
  LTDAVPLSVLILGLLIMFITIVFCAAGIVVLVLHRRRRYKKKQVDEQMRDNSPVHLQYSM
  YGHKTTHHTTERPSASLYEQHMVSPMVHVYRSPSFGPKHLEEEEERNEKEGSDAKHLQRS
  LLEQENHSPLTGSNMKYKTTNQSTEFLSFQDASSLYRNILEKERELQQLGITEYLRKNIA
  QLQPDMEAHYPGAHEELKLMETLMYSRPRKVLVEQTKNEYFELKANLHAEPDYLEVLEQQ
  T
• Function: Regulator of neurite outgrowth required for normal hearing and vision.
• Tissue Specificity: In adult brain, highly expressed in putamen with no expression in cerebral cortex. Expressed in adult and fetal lung and fetal liver. Also expressed at high levels in some brain tumors including medulloblastomas and primitive neuroectodermal tumors.
• KEGG Pathway: Cell adhesion molecules (hsa04514)
• Reactome Pathway: Receptor-type tyrosine-protein phosphatases (R-HSA-388844)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
High myopia-sensorineural deafness syndrome	DISG6HNS	Definitive	Autosomal recessive	[1]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[2]

9 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 SLIT and NTRK-like protein 6 (SLITRK6).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of SLIT and NTRK-like protein 6 (SLITRK6).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of SLIT and NTRK-like protein 6 (SLITRK6).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of SLIT and NTRK-like protein 6 (SLITRK6).	[6]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of SLIT and NTRK-like protein 6 (SLITRK6).	[6]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of SLIT and NTRK-like protein 6 (SLITRK6).	[7]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of SLIT and NTRK-like protein 6 (SLITRK6).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of SLIT and NTRK-like protein 6 (SLITRK6).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of SLIT and NTRK-like protein 6 (SLITRK6).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of SLIT and NTRK-like protein 6 (SLITRK6).	[9]

References

• [1] 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.
• [2] SLITRK6 mutations cause myopia and deafness in humans and mice. J Clin Invest. 2013 May;123(5):2094-102. doi: 10.1172/JCI65853. Epub 2013 Apr 1.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] 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.
• [6] 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.
• [7] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [8] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [9] 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.
• [10] 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.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.