Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0S9Z0J)

• DOT Name: Protein O-linked-mannose beta-1,4-N-acetylglucosaminyltransferase 2 (POMGNT2)
• Synonyms: POMGnT2; EC 2.4.1.312; Extracellular O-linked N-acetylglucosamine transferase-like; Glycosyltransferase-like domain-containing protein 2
• Gene Name: POMGNT2
• Related Disease:
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8
  Myopathy caused by variation in POMGNT2
  Limb-girdle muscular dystrophy
  Malaria
  Acute myelogenous leukaemia
  Hydrocephalus
  Muscular dystrophy
  Muscular dystrophy-dystroglycanopathy, type A
• UniProt ID: PMGT2_HUMAN
• PDB ID: 6XFI
• EC Number: 2.4.1.312
• Pfam ID: PF04577
• Sequence:
  MHLSAVFNALLVSVLAAVLWKHVRLREHAATLEEELALSRQATEPAPALRIDYPKALQIL
  MEGGTHMVCTGRTHTDRICRFKWLCYSNEAEEFIFFHGNTSVMLPNLGSRRFQPALLDLS
  TVEDHNTQYFNFVELPAAALRFMPKPVFVPDVALIANRFNPDNLMHVFHDDLLPLFYTLR
  QFPGLAHEARLFFMEGWGEGAHFDLYKLLSPKQPLLRAQLKTLGRLLCFSHAFVGLSKIT
  TWYQYGFVQPQGPKANILVSGNEIRQFARFMTEKLNVSHTGVPLGEEYILVFSRTQNRLI
  LNEAELLLALAQEFQMKTVTVSLEDHTFADVVRLVSNASMLVSMHGAQLVTTLFLPRGAT
  VVELFPYAVNPDHYTPYKTLAMLPGMDLQYVAWRNMMPENTVTHPERPWDQGGITHLDRA
  EQARILQSREVPRHLCCRNPEWLFRIYQDTKVDIPSLIQTIRRVVKGRPGPRKQKWTVGL
  YPGKVREARCQASVHGASEARLTVSWQIPWNLKYLKVREVKYEVWLQEQGENTYVPYILA
  LQNHTFTENIKPFTTYLVWVRCIFNKILLGPFADVLVCNT
• Function: O-linked mannose beta-1,4-N-acetylglucosaminyltransferase that transfers UDP-N-acetyl-D-glucosamine to the 4-position of the mannose to generate N-acetyl-D-glucosamine-beta-1,4-O-D-mannosylprotein. Involved in the biosynthesis of the phosphorylated O-mannosyl trisaccharide (N-acetylgalactosamine-beta-3-N-acetylglucosamine-beta-4-(phosphate-6-)mannose), a carbohydrate structure present in alpha-dystroglycan (DAG1), which is required for binding laminin G-like domain-containing extracellular proteins with high affinity.
• Tissue Specificity: Highly expressed in the brain, muscle, heart, and kidney in both fetus and adult. In the brain, highest expression in the cortex and cerebellum. Highly expressed in the pancreas.
• KEGG Pathway:
  Mannose type O-glycan biosynthesis (hsa00515)
  Metabolic pathways (hsa01100)
• Reactome Pathway: O-linked glycosylation (R-HSA-5173105)
• BioCyc Pathway: MetaCyc:ENSG00000144647-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8	DIS3EQX0	Definitive	Autosomal recessive	[1]
Myopathy caused by variation in POMGNT2	DISE9GAB	Definitive	Autosomal recessive	[2]
Limb-girdle muscular dystrophy	DISI9Y1Z	Strong	Biomarker	[3]
Malaria	DISQ9Y50	Strong	Genetic Variation	[4]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[5]
Hydrocephalus	DISIZUF7	moderate	Biomarker	[1]
Muscular dystrophy	DISJD6P7	moderate	Biomarker	[1]
Muscular dystrophy-dystroglycanopathy, type A	DISZTBC4	Supportive	Autosomal recessive	[1]

6 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 Protein O-linked-mannose beta-1,4-N-acetylglucosaminyltransferase 2 (POMGNT2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein O-linked-mannose beta-1,4-N-acetylglucosaminyltransferase 2 (POMGNT2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein O-linked-mannose beta-1,4-N-acetylglucosaminyltransferase 2 (POMGNT2).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Protein O-linked-mannose beta-1,4-N-acetylglucosaminyltransferase 2 (POMGNT2).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein O-linked-mannose beta-1,4-N-acetylglucosaminyltransferase 2 (POMGNT2).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Protein O-linked-mannose beta-1,4-N-acetylglucosaminyltransferase 2 (POMGNT2).	[12]

2 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 Protein O-linked-mannose beta-1,4-N-acetylglucosaminyltransferase 2 (POMGNT2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein O-linked-mannose beta-1,4-N-acetylglucosaminyltransferase 2 (POMGNT2).	[13]

References

• [1] Exome sequencing and functional validation in zebrafish identify GTDC2 mutations as a cause of Walker-Warburg syndrome. Am J Hum Genet. 2012 Sep 7;91(3):541-7. doi: 10.1016/j.ajhg.2012.07.009.
• [2] 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.
• [3] Milder forms of muscular dystrophy associated with POMGNT2 mutations.Neurol Genet. 2015 Dec 10;1(4):e33. doi: 10.1212/NXG.0000000000000033. eCollection 2015 Dec.
• [4] Genome-wide and fine-resolution association analysis of malaria in West Africa.Nat Genet. 2009 Jun;41(6):657-65. doi: 10.1038/ng.388. Epub 2009 May 24.
• [5] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.