Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDX7GZD)

• DOT Name: Protein O-glucosyltransferase 1 (POGLUT1)
• Synonyms: EC 2.4.1.376; CAP10-like 46 kDa protein; hCLP46; KTEL motif-containing protein 1; Myelodysplastic syndromes relative protein; O-glucosyltransferase Rumi homolog; hRumi; Protein O-xylosyltransferase POGLUT1; EC 2.4.2.63
• Gene Name: POGLUT1
• Related Disease:
  Autosomal recessive limb-girdle muscular dystrophy
  Primary biliary cholangitis
  Advanced cancer
  Autosomal recessive limb-girdle muscular dystrophy type 2R1
  Childhood myelodysplastic syndrome
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Dowling-Degos disease 4
  Hematologic disease
  leukaemia
  Leukemia
  Muscular dystrophy
  Myelodysplastic syndrome
  Neoplasm
  Non-small-cell lung cancer
  Limb-girdle muscular dystrophy
  Dowling-Degos disease
  Acute myelogenous leukaemia
  Darier disease
  T-cell acute lymphoblastic leukaemia
• UniProt ID: PGLT1_HUMAN
• PDB ID: 5L0R; 5L0S; 5L0T; 5L0U; 5L0V; 5UB5
• EC Number: 2.4.1.376; 2.4.2.63
• Pfam ID: PF05686
• Sequence:
  MEWWASSPLRLWLLLFLLPSAQGRQKESGSKWKVFIDQINRSLENYEPCSSQNCSCYHGV
  IEEDLTPFRGGISRKMMAEVVRRKLGTHYQITKNRLYRENDCMFPSRCSGVEHFILEVIG
  RLPDMEMVINVRDYPQVPKWMEPAIPVFSFSKTSEYHDIMYPAWTFWEGGPAVWPIYPTG
  LGRWDLFREDLVRSAAQWPWKKKNSTAYFRGSRTSPERDPLILLSRKNPKLVDAEYTKNQ
  AWKSMKDTLGKPAAKDVHLVDHCKYKYLFNFRGVAASFRFKHLFLCGSLVFHVGDEWLEF
  FYPQLKPWVHYIPVKTDLSNVQELLQFVKANDDVAQEIAERGSQFIRNHLQMDDITCYWE
  NLLSEYSKFLSYNVTRRKGYDQIIPKMLKTEL
• Function: Dual specificity glycosyltransferase that catalyzes the transfer of glucose and xylose from UDP-glucose and UDP-xylose, respectively, to a serine residue found in the consensus sequence of C-X-S-X-P-C. Specifically targets extracellular EGF repeats of protein such as CRB2, F7, F9 and NOTCH2. Acts as a positive regulator of Notch signaling by mediating O-glucosylation of Notch, leading to regulate muscle development. Notch glucosylation does not affect Notch ligand binding. Required during early development to promote gastrulation: acts by mediating O-glucosylation of CRB2, which is required for CRB2 localization to the cell membrane.
• Tissue Specificity: Expressed in most adult tissues at different intensities. Abundantly expressed in liver. Expressed also in brain, heart, skeletal muscle, spleen, kidney, placenta, lung and peripheral blood leukocyte. Not detectable in colon, thymus and small intestine. Expressed in the epidermis, especially in the upper parts, stratum spinosum and stratum granulosum (at protein level).
• KEGG Pathway: Other types of O-glycan biosynthesis (hsa00514)
• Reactome Pathway: Pre-NOTCH Processing in the Endoplasmic Reticulum (R-HSA-1912399)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive limb-girdle muscular dystrophy	DISWPGLM	Definitive	Autosomal recessive	[1]
Primary biliary cholangitis	DIS43E0O	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Autosomal recessive limb-girdle muscular dystrophy type 2R1	DISZFHZ9	Strong	Autosomal recessive	[4]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Biomarker	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Dowling-Degos disease 4	DIS0ANW5	Strong	Autosomal dominant	[6]
Hematologic disease	DIS9XD9A	Strong	Biomarker	[7]
leukaemia	DISS7D1V	Strong	Altered Expression	[3]
Leukemia	DISNAKFL	Strong	Altered Expression	[3]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[8]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Limb-girdle muscular dystrophy	DISI9Y1Z	moderate	Genetic Variation	[10]
Dowling-Degos disease	DISGTTEP	Supportive	Autosomal dominant	[6]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[3]
Darier disease	DIS4WI7S	Limited	Biomarker	[11]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Limited	Altered Expression	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein O-glucosyltransferase 1 (POGLUT1).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein O-glucosyltransferase 1 (POGLUT1).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein O-glucosyltransferase 1 (POGLUT1).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein O-glucosyltransferase 1 (POGLUT1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein O-glucosyltransferase 1 (POGLUT1).	[17]

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 increases the methylation of Protein O-glucosyltransferase 1 (POGLUT1).	[16]

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] POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33.Sci Rep. 2019 Jan 14;9(1):102. doi: 10.1038/s41598-018-36490-1.
• [3] Human CAP10-Like Protein 46kDa Gene Promotes Malignancy in Colorectal Cancer.OMICS. 2017 May;21(5):266-274. doi: 10.1089/omi.2017.0037.
• [4] POGLUT1 biallelic mutations cause myopathy with reduced satellite cells, -dystroglycan hypoglycosylation and a distinctive radiological pattern. Acta Neuropathol. 2020 Mar;139(3):565-582. doi: 10.1007/s00401-019-02117-6. Epub 2020 Jan 3.
• [5] Overexpression of human CAP10-like protein 46 KD in T-acute lymphoblastic leukemia and acute myelogenous leukemia.Genet Test Mol Biomarkers. 2010 Feb;14(1):127-33. doi: 10.1089/gtmb.2009.0145.
• [6] Mutations in POGLUT1, encoding protein O-glucosyltransferase 1, cause autosomal-dominant Dowling-Degos disease. Am J Hum Genet. 2014 Jan 2;94(1):135-43. doi: 10.1016/j.ajhg.2013.12.003.
• [7] hCLP46 regulates U937 cell proliferation via Notch signaling pathway.Biochem Biophys Res Commun. 2011 Apr 29;408(1):84-8. doi: 10.1016/j.bbrc.2011.03.124. Epub 2011 Mar 31.
• [8] A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss. EMBO Mol Med. 2016 Nov 2;8(11):1289-1309. doi: 10.15252/emmm.201505815. Print 2016 Nov.
• [9] RUMI is a novel negative prognostic marker and therapeutic target in non-small-cell lung cancer.J Cell Physiol. 2018 Dec;233(12):9548-9562. doi: 10.1002/jcp.26858. Epub 2018 Jun 28.
• [10] Generation of an induced pluripotent stem cell line (CSCRMi001-A) from a patient with a new type of limb-girdle muscular dystrophy (LGMD) due to a missense mutation in POGLUT1 (Rumi).Stem Cell Res. 2017 Oct;24:102-105. doi: 10.1016/j.scr.2017.08.020. Epub 2017 Sep 1.
• [11] Dowling-Degos disease co-presenting with Darier disease.Clin Exp Dermatol. 2016 Jun;41(4):410-2. doi: 10.1111/ced.12790. Epub 2015 Dec 18.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] 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.
• [17] 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.