Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOF6O2B)

• DOT Name: UDP-GalNAc:beta-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2)
• Synonyms: Beta-1,3-GalNAc-T2; EC 2.4.1.313; Beta-1,3-N-acetylgalactosaminyltransferase II
• Gene Name: B3GALNT2
• Related Disease:
  Breast cancer
  Congenital muscular dystrophy
  Muscular dystrophy
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 11
  Sensorineural hearing loss disorder
  Autosomal recessive non-syndromic intellectual disability
  Muscle-eye-brain disease
  Muscular dystrophy-dystroglycanopathy, type A
  Hydrocephalus
  Advanced cancer
  Breast carcinoma
  Hepatocellular carcinoma
  Intellectual disability
  Neoplasm
• UniProt ID: B3GL2_HUMAN
• EC Number: 2.4.1.313
• Pfam ID: PF01762
• Sequence:
  MRNWLVLLCPCVLGAALHLWLRLRSPPPACASGAGPADQLALFPQWKSTHYDVVVGVLSA
  RNNHELRNVIRSTWMRHLLQHPTLSQRVLVKFIIGAHGCEVPVEDREDPYSCKLLNITNP
  VLNQEIEAFSLSEDTSSGLPEDRVVSVSFRVLYPIVITSLGVFYDANDVGFQRNITVKLY
  QAEQEEALFIARFSPPSCGVQVNKLWYKPVEQFILPESFEGTIVWESQDLHGLVSRNLHK
  VTVNDGGGVLRVITAGEGALPHEFLEGVEGVAGGFIYTIQEGDALLHNLHSRPQRLIDHI
  RNLHEEDALLKEESSIYDDIVFVDVVDTYRNVPAKLLNFYRWTVETTSFNLLLKTDDDCY
  IDLEAVFNRIVQKNLDGPNFWWGNFRLNWAVDRTGKWQELEYPSPAYPAFACGSGYVISK
  DIVKWLASNSGRLKTYQGEDVSMGIWMAAIGPKRYQDSLWLCEKTCETGMLSSPQYSPWE
  LTELWKLKERCGDPCRCQAR
• Function: Beta-1,3-N-acetylgalactosaminyltransferase that synthesizes a unique carbohydrate structure, GalNAc-beta-1-3GlcNAc, on N- and O-glycans. Has no galactose nor galactosaminyl transferase activity toward any acceptor substrate. Involved in alpha-dystroglycan (DAG1) glycosylation: acts coordinately with GTDC2/POMGnT2 to synthesize a GalNAc-beta3-GlcNAc-beta-terminus at the 4-position of protein O-mannose 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, which is required for binding laminin G-like domain-containing extracellular proteins with high affinity.
• Tissue Specificity: Expressed in all tissues examined, but at highest levels in testis, adipose tissue, skeletal muscle and ovary.
• KEGG Pathway:
  Mannose type O-glycan biosynthesis (hsa00515)
  Metabolic pathways (hsa01100)
• Reactome Pathway: O-linked glycosylation (R-HSA-5173105)
• BioCyc Pathway: MetaCyc:ENSG00000162885-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Congenital muscular dystrophy	DISKY7OY	Strong	Genetic Variation	[2]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[3]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 11	DISTNH1Q	Strong	Autosomal recessive	[4]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[5]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[3]
Muscle-eye-brain disease	DISJUOQB	Supportive	Autosomal recessive	[6]
Muscular dystrophy-dystroglycanopathy, type A	DISZTBC4	Supportive	Autosomal recessive	[6]
Hydrocephalus	DISIZUF7	Disputed	Genetic Variation	[7]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[8]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[8]
Intellectual disability	DISMBNXP	Limited	Autosomal recessive	[9]
Neoplasm	DISZKGEW	Limited	Altered Expression	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of UDP-GalNAc:beta-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2).	[10]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of UDP-GalNAc:beta-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of UDP-GalNAc:beta-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of UDP-GalNAc:beta-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of UDP-GalNAc:beta-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2).	[14]

References

• [1] Involvement of B3GALNT2 overexpression in the cell growth of breast cancer.Int J Oncol. 2014 Feb;44(2):427-34. doi: 10.3892/ijo.2013.2187. Epub 2013 Nov 27.
• [2] Serial prenatal and postnatal MRI of dystroglycanopathy in a patient with familial B3GALNT2 mutation.Pediatr Radiol. 2017 Jun;47(7):884-888. doi: 10.1007/s00247-017-3821-1. Epub 2017 Mar 16.
• [3] B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype-phenotype associations in the muscular dystrophy-dystroglycanopathies. Genome Med. 2017 Dec 22;9(1):118. doi: 10.1186/s13073-017-0505-2.
• [4] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [5] B3GALNT2-Related Dystroglycanopathy: Expansion of the Phenotype with Novel Mutation Associated with Muscle-Eye-Brain Disease, Walker-Warburg Syndrome, Epileptic Encephalopathy-West Syndrome, and Sensorineural Hearing Loss. Neuropediatrics. 2018 Aug;49(4):289-295. doi: 10.1055/s-0038-1651519. Epub 2018 May 23.
• [6] Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of -dystroglycan. Am J Hum Genet. 2013 Mar 7;92(3):354-65. doi: 10.1016/j.ajhg.2013.01.016. Epub 2013 Feb 28.
• [7] Genotyping of friesian horses to detect a hydrocephalus-associated c.1423C>T mutation in B3GALNT2 using PCR-RFLP and PCR-PIRA methods: Frequency in stallion horses in Mxico.Mol Cell Probes. 2017 Apr;32:69-71. doi: 10.1016/j.mcp.2016.12.005. Epub 2016 Dec 21.
• [8] Increased B3GALNT2 in hepatocellular carcinoma promotes macrophage recruitment via reducing acetoacetate secretion and elevating MIF activity.J Hematol Oncol. 2018 Apr 4;11(1):50. doi: 10.1186/s13045-018-0595-3.
• [9] 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.
• [10] 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.
• [11] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [12] 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.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [14] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.