Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTG8MAK)

• DOT Name: Torsin-1A-interacting protein 1 (TOR1AIP1)
• Synonyms: Lamin-associated protein 1B; LAP1B
• Gene Name: TOR1AIP1
• Related Disease:
  Dystonia
  Autosomal recessive limb-girdle muscular dystrophy type 2Y
  Candidiasis
  Cardiac failure
  Congestive heart failure
  Dilated cardiomyopathy
  Fatty liver disease
  Hepatocellular carcinoma
  Herpes simplex infection
  Limb-girdle muscular dystrophy
  Non-alcoholic fatty liver disease
  Open-angle glaucoma
  Qualitative or quantitative defects of dysferlin
  X-linked Emery-Dreifuss muscular dystrophy
  Muscular dystrophy
  Cardiomyopathy
• UniProt ID: TOIP1_HUMAN
• PDB ID: 4TVS
• Pfam ID: PF05609 ; PF20443
• Sequence:
  MAGDGRRAEAVREGWGVYVTPRAPIREGRGRLAPQNGGSSDAPAYRTPPSRQGRREVRFS
  DEPPEVYGDFEPLVAKERSPVGKRTRLEEFRSDSAKEEVRESAYYLRSRQRRQPRPQETE
  EMKTRRTTRLQQQHSEQPPLQPSPVMTRRGLRDSHSSEEDEASSQTDLSQTISKKTVRSI
  QEAPVSEDLVIRLRRPPLRYPRYEATSVQQKVNFSEEGETEEDDQDSSHSSVTTVKARSR
  DSDESGDKTTRSSSQYIESFWQSSQSQNFTAHDKQPSVLSSGYQKTPQEWAPQTARIRTR
  MQNDSILKSELGNQSPSTSSRQVTGQPQNASFVKRNRWWLLPLIAALASGSFWFFSTPEV
  ETTAVQEFQNQMNQLKNKYQGQDEKLWKRSQTFLEKHLNSSHPRSQPAILLLTAARDAEE
  ALRCLSEQIADAYSSFRSVRAIRIDGTDKATQDSDTVKLEVDQELSNGFKNGQNAAVVHR
  FESFPAGSTLIFYKYCDHENAAFKDVALVLTVLLEEETLGTSLGLKEVEEKVRDFLKVKF
  TNSNTPNSYNHMDPDKLNGLWSRISHLVLPVQPENALKRGICL
• Function: Required for nuclear membrane integrity. Induces TOR1A and TOR1B ATPase activity and is required for their location on the nuclear membrane. Binds to A- and B-type lamins. Possible role in membrane attachment and assembly of the nuclear lamina.
• Tissue Specificity: Expressed in muscle, liver and kidney.; [Isoform 1]: Major isoform present in liver, brain and heart (at protein level). Expressed at lower levels than isoform 4 in lung, kidney and spleen (at protein level). Similar levels of isoforms 1 and 4 are observed in ovary, testis and pancreas (at protein level).; [Isoform 4]: Expressed at higher levels than isoform 1 in lung, kidney and spleen (at protein level). Expressed at lower levels than isoform 1 in liver, brain and heart (at protein level). Similar levels of isoforms 1 and 4 are observed in ovary, testis and pancreas (at protein level).
• Reactome Pathway:
  RHOF GTPase cycle (R-HSA-9035034)
  RHOD GTPase cycle (R-HSA-9013405)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dystonia	DISJLFGW	Definitive	Biomarker	[1]
Autosomal recessive limb-girdle muscular dystrophy type 2Y	DISHF17L	Strong	Autosomal recessive	[2]
Candidiasis	DISIRYMU	Strong	Altered Expression	[3]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Dilated cardiomyopathy	DISX608J	Strong	Biomarker	[4]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Herpes simplex infection	DISL1SAV	Strong	Altered Expression	[7]
Limb-girdle muscular dystrophy	DISI9Y1Z	Strong	Biomarker	[8]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[9]
Open-angle glaucoma	DISSZEE8	Strong	Genetic Variation	[10]
Qualitative or quantitative defects of dysferlin	DIS59VEJ	Strong	Biomarker	[11]
X-linked Emery-Dreifuss muscular dystrophy	DISDPMZ3	Strong	Biomarker	[12]
Muscular dystrophy	DISJD6P7	moderate	Biomarker	[8]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[13]

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 Torsin-1A-interacting protein 1 (TOR1AIP1).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Torsin-1A-interacting protein 1 (TOR1AIP1).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Torsin-1A-interacting protein 1 (TOR1AIP1).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Torsin-1A-interacting protein 1 (TOR1AIP1).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Torsin-1A-interacting protein 1 (TOR1AIP1).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Torsin-1A-interacting protein 1 (TOR1AIP1).	[19]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Torsin-1A-interacting protein 1 (TOR1AIP1).	[19]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Torsin-1A-interacting protein 1 (TOR1AIP1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Torsin-1A-interacting protein 1 (TOR1AIP1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Torsin-1A-interacting protein 1 (TOR1AIP1).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Torsin-1A-interacting protein 1 (TOR1AIP1).	[22]

References

• [1] Genetic mutations strengthen functional association of LAP1 with DYT1 dystonia and muscular dystrophy.Mutat Res Rev Mutat Res. 2015 Oct-Dec;766:42-7. doi: 10.1016/j.mrrev.2015.07.004. Epub 2015 Aug 5.
• [2] Lamina-associated polypeptide-1 interacts with the muscular dystrophy protein emerin and is essential for skeletal muscle maintenance. Dev Cell. 2013 Sep 30;26(6):591-603. doi: 10.1016/j.devcel.2013.08.012. Epub 2013 Sep 19.
• [3] In vitro investigation on probiotic, anti-Candida, and antibiofilm properties of Lactobacillus pentosus strain LAP1.Arch Oral Biol. 2018 May;89:99-106. doi: 10.1016/j.archoralbio.2018.02.014. Epub 2018 Feb 23.
• [4] TOR1AIP1 as a cause of cardiac failure and recessive limb-girdle muscular dystrophy.Neuromuscul Disord. 2016 Aug;26(8):500-3. doi: 10.1016/j.nmd.2016.05.013. Epub 2016 May 24.
• [5] An unbiased approach de-livers unexpected insight into torsin biology.J Clin Invest. 2019 Nov 1;129(11):4576-4579. doi: 10.1172/JCI132442.
• [6] Orosomucoid 2 inhibits tumor metastasis and is upregulated by CCAAT/enhancer binding protein in hepatocellular carcinomas.Oncotarget. 2015 Jun 30;6(18):16106-19. doi: 10.18632/oncotarget.3867.
• [7] cis-acting elements involved in transcriptional regulation of the herpes simplex virus type 1 latency-associated promoter 1 (LAP1) in vitro and in vivo.J Virol. 1996 Aug;70(8):5384-94. doi: 10.1128/JVI.70.8.5384-5394.1996.
• [8] Magnetic Resonance Imaging characteristics in case of TOR1AIP1 muscular dystrophy.Clin Imaging. 2019 Nov-Dec;58:108-113. doi: 10.1016/j.clinimag.2019.06.010. Epub 2019 Jun 21.
• [9] Nuclear envelope-localized torsinA-LAP1 complex regulates hepatic VLDL secretion and steatosis.J Clin Invest. 2019 Aug 13;129(11):4885-4900. doi: 10.1172/JCI129769.
• [10] Common variants in CDKN2B-AS1 associated with optic-nerve vulnerability of glaucoma identified by genome-wide association studies in Japanese.PLoS One. 2012;7(3):e33389. doi: 10.1371/journal.pone.0033389. Epub 2012 Mar 12.
• [11] Gene co-expression network analysis of dysferlinopathy: Altered cellular processes and functional prediction of TOR1AIP1, a novel muscular dystrophy gene.Neuromuscul Disord. 2017 Mar;27(3):269-277. doi: 10.1016/j.nmd.2016.10.011. Epub 2016 Nov 3.
• [12] Identification of a novel human LAP1 isoform that is regulated by protein phosphorylation.PLoS One. 2014 Dec 2;9(12):e113732. doi: 10.1371/journal.pone.0113732. eCollection 2014.
• [13] Severe dystonia, cerebellar atrophy, and cardiomyopathy likely caused by a missense mutation in TOR1AIP1.Orphanet J Rare Dis. 2014 Nov 26;9:174. doi: 10.1186/s13023-014-0174-9.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [16] 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.
• [17] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [18] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [19] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [20] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [21] 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.
• [22] 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.