Details of Drug Off-Target (DOT)

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

• DOT Name: Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1)
• Synonyms: POMGnT1; EC 2.4.1.-; UDP-GlcNAc:alpha-D-mannoside beta-1,2-N-acetylglucosaminyltransferase I.2; GnT I.2
• Gene Name: POMGNT1
• Related Disease:
  Autosomal recessive limb-girdle muscular dystrophy type 2O
  Muscle-eye-brain disease
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3
  Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3
  Non-insulin dependent diabetes
  Adult glioblastoma
  Autism spectrum disorder
  Central core myopathy
  Congenital fiber-type disproportion myopathy
  Congenital muscular dystrophy
  Congenital myopathy
  Deafness
  Glioblastoma multiforme
  Limb-girdle muscular dystrophy due to POMK deficiency
  Medulloblastoma
  Multiminicore myopathy
  Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2
  Myopathy caused by variation in POMGNT1
  Nemaline myopathy
  Retinitis pigmentosa 76
  Hydrocephalus
  Isolated congenital microcephaly
  Neuroblastoma
  Retinopathy
  Muscular dystrophy-dystroglycanopathy, type A
  Obsolete congenital muscular dystrophy with cerebellar involvement
  Retinitis pigmentosa
  Intellectual disability
  Muscular dystrophy
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4
• UniProt ID: PMGT1_HUMAN
• PDB ID: 5GGF; 5GGG; 5GGI; 5GGJ; 5GGK; 5GGL; 5GGN; 5GGO; 5GGP; 5XFC
• EC Number: 2.4.1.-
• Pfam ID: PF03071 ; PF15711
• Sequence:
  MDDWKPSPLIKPFGARKKRSWYLTWKYKLTNQRALRRFCQTGAVLFLLVTVIVNIKLILD
  TRRAISEANEDPEPEQDYDEALGRLEPPRRRGSGPRRVLDVEVYSSRSKVYVAVDGTTVL
  EDEAREQGRGIHVIVLNQATGHVMAKRVFDTYSPHEDEAMVLFLNMVAPGRVLICTVKDE
  GSFHLKDTAKALLRSLGSQAGPALGWRDTWAFVGRKGGPVFGEKHSKSPALSSWGDPVLL
  KTDVPLSSAEEAECHWADTELNRRRRRFCSKVEGYGSVCSCKDPTPIEFSPDPLPDNKVL
  NVPVAVIAGNRPNYLYRMLRSLLSAQGVSPQMITVFIDGYYEEPMDVVALFGLRGIQHTP
  ISIKNARVSQHYKASLTATFNLFPEAKFAVVLEEDLDIAVDFFSFLSQSIHLLEEDDSLY
  CISAWNDQGYEHTAEDPALLYRVETMPGLGWVLRRSLYKEELEPKWPTPEKLWDWDMWMR
  MPEQRRGRECIIPDVSRSYHFGIVGLNMNGYFHEAYFKKHKFNTVPGVQLRNVDSLKKEA
  YEVEVHRLLSEAEVLDHSKNPCEDSFLPDTEGHTYVAFIRMEKDDDFTTWTQLAKCLHIW
  DLDVRGNHRGLWRLFRKKNHFLMVGVPASPYSVKKPPSVTPIFLEPPPKEEGAPGAPEQT
• Function: Participates in O-mannosyl glycosylation by catalyzing the addition of N-acetylglucosamine to O-linked mannose on glycoproteins. Catalyzes the synthesis of the GlcNAc(beta1-2)Man(alpha1-)O-Ser/Thr moiety on alpha-dystroglycan and other O-mannosylated proteins, providing the necessary basis for the addition of further carbohydrate moieties. Is specific for alpha linked terminal mannose and does not have MGAT3, MGAT4, MGAT5, MGAT7 or MGAT8 activity.
• Tissue Specificity: Constitutively expressed. An additional weaker band is also detected in spinal cord, lymph node, and trachea. Expressed especially in astrocytes. Also expressed in immature and mature neurons.
• KEGG Pathway:
  Mannose type O-glycan biosynthesis (hsa00515)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  O-linked glycosylation (R-HSA-5173105)
  Defective POMGNT1 causes MDDGA3, MDDGB3 and MDDGC3 (R-HSA-5083628)
• BioCyc Pathway: MetaCyc:ENSG00000085998-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive limb-girdle muscular dystrophy type 2O	DISOYA4X	Definitive	Autosomal recessive	[1]
Muscle-eye-brain disease	DISJUOQB	Definitive	Autosomal recessive	[2]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3	DIS95RCP	Definitive	Autosomal recessive	[3]
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	DISSP7OL	Definitive	Autosomal recessive	[4]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[5]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[6]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[7]
Central core myopathy	DIS18AZZ	Strong	Biomarker	[8]
Congenital fiber-type disproportion myopathy	DISU9T2M	Strong	Biomarker	[8]
Congenital muscular dystrophy	DISKY7OY	Strong	Genetic Variation	[9]
Congenital myopathy	DISLSK9G	Strong	Biomarker	[8]
Deafness	DISKCLH4	Strong	Genetic Variation	[10]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[6]
Limb-girdle muscular dystrophy due to POMK deficiency	DISM63SY	Strong	Biomarker	[8]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[6]
Multiminicore myopathy	DISE6VYN	Strong	Biomarker	[8]
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2	DIS2BGID	Strong	Biomarker	[8]
Myopathy caused by variation in POMGNT1	DIS0B8FY	Strong	Autosomal recessive	[2]
Nemaline myopathy	DIS5IYLY	Strong	Biomarker	[8]
Retinitis pigmentosa 76	DISC06NY	Strong	Autosomal recessive	[11]
Hydrocephalus	DISIZUF7	moderate	Genetic Variation	[11]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[12]
Neuroblastoma	DISVZBI4	moderate	Altered Expression	[13]
Retinopathy	DISB4B0F	moderate	Genetic Variation	[14]
Muscular dystrophy-dystroglycanopathy, type A	DISZTBC4	Supportive	Autosomal recessive	[15]
Obsolete congenital muscular dystrophy with cerebellar involvement	DIS8CGS1	Supportive	Autosomal recessive	[16]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[17]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[18]
Muscular dystrophy	DISJD6P7	Limited	Biomarker	[14]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	DISGM0K5	Limited	Biomarker	[19]

9 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 Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1).	[20]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1).	[24]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1).	[25]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1).	[26]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1).	[29]

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 affects the methylation of Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1).	[28]

References

• [1] Promoter alteration causes transcriptional repression of the POMGNT1 gene in limb-girdle muscular dystrophy type 2O. Eur J Hum Genet. 2012 Sep;20(9):945-52. doi: 10.1038/ejhg.2012.40. Epub 2012 Mar 14.
• [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] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain. 2007 Oct;130(Pt 10):2725-35. doi: 10.1093/brain/awm212. Epub 2007 Sep 18.
• [5] Generalization of Rare Variant Association Tests for Longitudinal Family Studies.Genet Epidemiol. 2016 Feb;40(2):101-12. doi: 10.1002/gepi.21951. Epub 2016 Jan 18.
• [6] Decrease of Nibrin expression in chronic hypoxia is associated with hypoxia-induced chemoresistance in some brain tumour cells.BMC Cancer. 2019 Apr 3;19(1):300. doi: 10.1186/s12885-019-5476-9.
• [7] Using whole-exome sequencing to identify inherited causes of autism.Neuron. 2013 Jan 23;77(2):259-73. doi: 10.1016/j.neuron.2012.11.002.
• [8] Degree of Cajal-Retzius Cell Mislocalization Correlates with the Severity of Structural Brain Defects in Mouse Models of Dystroglycanopathy.Brain Pathol. 2016 Jul;26(4):465-78. doi: 10.1111/bpa.12306. Epub 2015 Oct 12.
• [9] Novel synonymous substitution in POMGNT1 promotes exon skipping in a patient with congenital muscular dystrophy.J Hum Genet. 2008;53(6):565-572. doi: 10.1007/s10038-008-0263-5. Epub 2008 Mar 11.
• [10] GG: a domain involved in phage LTF apparatus and implicated in human MEB and non-syndromic hearing loss diseases.FEBS Lett. 2006 Jan 23;580(2):581-4. doi: 10.1016/j.febslet.2005.12.076. Epub 2006 Jan 3.
• [11] Worldwide distribution and broader clinical spectrum of muscle-eye-brain disease. Hum Mol Genet. 2003 Mar 1;12(5):527-34. doi: 10.1093/hmg/ddg043.
• [12] A 649 kb microduplication in 1p34.1, including POMGNT1, in a patient with microcephaly, coloboma and laryngomalacia; and a review of the literature.Eur J Med Genet. 2009 Mar-Jun;52(2-3):116-9. doi: 10.1016/j.ejmg.2009.01.005.
• [13] Integrin-dependent neuroblastoma cell adhesion and migration on laminin is regulated by expression levels of two enzymes in the O-mannosyl-linked glycosylation pathway, PomGnT1 and GnT-Vb.Exp Cell Res. 2006 Sep 10;312(15):2837-50. doi: 10.1016/j.yexcr.2006.05.022. Epub 2006 Jun 21.
• [14] Homozygosity Mapping and Whole-Genome Sequencing Links a Missense Mutation in POMGNT1 to Autosomal Recessive Retinitis Pigmentosa.Invest Ophthalmol Vis Sci. 2016 Jul 1;57(8):3601-9. doi: 10.1167/iovs.16-19463.
• [15] Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. Neurology. 2009 May 26;72(21):1802-9. doi: 10.1212/01.wnl.0000346518.68110.60. Epub 2009 Mar 18.
• [16] Dystroglycanopathies: coming into focus. Curr Opin Genet Dev. 2011 Jun;21(3):278-85. doi: 10.1016/j.gde.2011.02.001. Epub 2011 Mar 11.
• [17] Mutations in POMGNT1 cause non-syndromic retinitis pigmentosa. Hum Mol Genet. 2016 Apr 15;25(8):1479-88. doi: 10.1093/hmg/ddw022. Epub 2016 Jan 28.
• [18] Mild POMGnT1 mutations underlie a novel limb-girdle muscular dystrophy variant.Arch Neurol. 2008 Jan;65(1):137-41. doi: 10.1001/archneurol.2007.2.
• [19] Fukuyama-type congenital muscular dystrophy (FCMD) and alpha-dystroglycanopathy.Congenit Anom (Kyoto). 2003 Jun;43(2):97-104. doi: 10.1111/j.1741-4520.2003.tb01033.x.
• [20] 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.
• [21] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [22] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [25] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [26] 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.
• [27] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [28] 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.
• [29] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.