Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH3V9L1)

• DOT Name: Myotubularin-related protein 12 (MTMR12)
• Synonyms: Inactive phosphatidylinositol 3-phosphatase 12; Phosphatidylinositol 3 phosphate 3-phosphatase adapter subunit; 3-PAP; 3-phosphatase adapter protein
• Gene Name: MTMR12
• Related Disease:
  Major depressive disorder
  Centronuclear myopathy
  Congenital structural myopathy
  X-linked myotubular myopathy
• UniProt ID: MTMRC_HUMAN
• Pfam ID: PF12578 ; PF06602
• Sequence:
  MLGKGVVGGGGGTKAPKPSFVSYVRPEEIHTNEKEVTEKEVTLHLLPGEQLLCEASTVLK
  YVQEDSCQHGVYGRLVCTDFKIAFLGDDESALDNDETQFKNKVIGENDITLHCVDQIYGV
  FDEKKKTLFGQLKKYPEKLIIHCKDLRVFQFCLRYTKEEEVKRIVSGIIHHTQAPKLLKR
  LFLFSYATAAQNNTVTDPKNHTVMFDTLKDWCWELERTKGNMKYKAVSVNEGYKVCERLP
  AYFVVPTPLPEENVQRFQGHGIPIWCWSCHNGSALLKMSALPKEQDDGILQIQKSFLDGI
  YKTIHRPPYEIVKTEDLSSNFLSLQEIQTAYSKFKQLFLIDNSTEFWDTDIKWFSLLESS
  SWLDIIRRCLKKAIEITECMEAQNMNVLLLEENASDLCCLISSLVQLMMDPHCRTRIGFQ
  SLIQKEWVMGGHCFLDRCNHLRQNDKEEVPVFLLFLDCVWQLVHQHPPAFEFTETYLTVL
  SDSLYIPIFSTFFFNSPHQKDTNMGREGQDTQSKPLNLLTVWDWSVQFEPKAQTLLKNPL
  YVEKPKLDKGQRKGMRFKHQRQLSLPLTQSKSSPKRGFFREETDHLIKNLLGKRISKLIN
  SSDELQDNFREFYDSWHSKSTDYHGLLLPHIEGPEIKVWAQRYLRWIPEAQILGGGQVAT
  LSKLLEMMEEVQSLQEKIDERHHSQQAPQAEAPCLLRNSARLSSLFPFALLQRHSSKPVL
  PTSGWKALGDEDDLAKREDEFVDLGDV
• Function: Acts as an adapter for the myotubularin-related phosphatases. Regulates phosphatase MTM1 protein stability and possibly its intracellular location. By stabilizing MTM1 protein levels, required for skeletal muscle maintenance but not for myogenesis.
• Tissue Specificity: Expressed in skeletal muscles (at protein level) . Ubiquitous with prominent expression in brain, heart, kidney, placenta, and lung .
• Reactome Pathway: Synthesis of PIPs at the early endosome membrane (R-HSA-1660516)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[1]
Centronuclear myopathy	DISXBEJO	Limited	Biomarker	[2]
Congenital structural myopathy	DISZ9JP4	Limited	Biomarker	[2]
X-linked myotubular myopathy	DISJ95GS	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Myotubularin-related protein 12 (MTMR12).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Myotubularin-related protein 12 (MTMR12).	[4]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Myotubularin-related protein 12 (MTMR12).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Myotubularin-related protein 12 (MTMR12).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Myotubularin-related protein 12 (MTMR12).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Myotubularin-related protein 12 (MTMR12).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Myotubularin-related protein 12 (MTMR12).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Myotubularin-related protein 12 (MTMR12).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Myotubularin-related protein 12 (MTMR12).	[9]

References

• [1] The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response.Transl Psychiatry. 2015 Apr 21;5(4):e553. doi: 10.1038/tp.2015.47.
• [2] Loss of catalytically inactive lipid phosphatase myotubularin-related protein 12 impairs myotubularin stability and promotes centronuclear myopathy in zebrafish.PLoS Genet. 2013 Jun;9(6):e1003583. doi: 10.1371/journal.pgen.1003583. Epub 2013 Jun 20.
• [3] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [4] 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.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [7] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [8] 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.
• [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] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.