Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBM7K28)

• DOT Name: UDP-N-acetylglucosamine transferase subunit ALG14 homolog (ALG14)
• Gene Name: ALG14
• Related Disease:
  Congenital myasthenic syndrome
  Congenital myasthenic syndrome 15
  Intellectual disability
  Myopathy, epilepsy, and progressive cerebral atrophy
  Obsolete congenital myasthenic syndromes with glycosylation defect
  Congenital disorder of glycosylation
• UniProt ID: ALG14_HUMAN
• Pfam ID: PF08660
• Sequence:
  MVCVLVLAAAAGAVAVFLILRIWVVLRSMDVTPRESLSILVVAGSGGHTTEILRLLGSLS
  NAYSPRHYVIADTDEMSANKINSFELDRADRDPSNMYTKYYIHRIPRSREVQQSWPSTVF
  TTLHSMWLSFPLIHRVKPDLVLCNGPGTCVPICVSALLLGILGIKKVIIVYVESICRVET
  LSMSGKILFHLSDYFIVQWPALKEKYPKSVYLGRIV
• Function: Involved in protein N-glycosylation. May play a role in the second step of the dolichol-linked oligosaccharide pathway. May anchor the catalytic subunit ALG13 to the ER.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Various types of N-glycan biosynthesis (hsa00513)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective ALG14 causes ALG14-CMS (R-HSA-5633231)
  Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein (R-HSA-446193)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital myasthenic syndrome	DISJLG2T	Strong	Biomarker	[1]
Congenital myasthenic syndrome 15	DIS41Z0P	Strong	Autosomal recessive	[2]
Intellectual disability	DISMBNXP	Strong	Biomarker	[3]
Myopathy, epilepsy, and progressive cerebral atrophy	DISEIX04	Strong	Autosomal recessive	[3]
Obsolete congenital myasthenic syndromes with glycosylation defect	DISIGACA	Supportive	Autosomal recessive	[1]
Congenital disorder of glycosylation	DIS400QP	Limited	Autosomal recessive	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of UDP-N-acetylglucosamine transferase subunit ALG14 homolog (ALG14).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of UDP-N-acetylglucosamine transferase subunit ALG14 homolog (ALG14).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of UDP-N-acetylglucosamine transferase subunit ALG14 homolog (ALG14).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of UDP-N-acetylglucosamine transferase subunit ALG14 homolog (ALG14).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of UDP-N-acetylglucosamine transferase subunit ALG14 homolog (ALG14).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of UDP-N-acetylglucosamine transferase subunit ALG14 homolog (ALG14).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of UDP-N-acetylglucosamine transferase subunit ALG14 homolog (ALG14).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of UDP-N-acetylglucosamine transferase subunit ALG14 homolog (ALG14).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of UDP-N-acetylglucosamine transferase subunit ALG14 homolog (ALG14).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of UDP-N-acetylglucosamine transferase subunit ALG14 homolog (ALG14).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of UDP-N-acetylglucosamine transferase subunit ALG14 homolog (ALG14).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of UDP-N-acetylglucosamine transferase subunit ALG14 homolog (ALG14).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of UDP-N-acetylglucosamine transferase subunit ALG14 homolog (ALG14).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of UDP-N-acetylglucosamine transferase subunit ALG14 homolog (ALG14).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of UDP-N-acetylglucosamine transferase subunit ALG14 homolog (ALG14).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of UDP-N-acetylglucosamine transferase subunit ALG14 homolog (ALG14).	[20]

References

• [1] Congenital myasthenic syndromes due to mutations in ALG2 and ALG14. Brain. 2013 Mar;136(Pt 3):944-56. doi: 10.1093/brain/awt010. Epub 2013 Feb 11.
• [2] 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.
• [3] Early and lethal neurodegeneration with myasthenic and myopathic features: A new ALG14-CDG. Neurology. 2017 Aug 15;89(7):657-664. doi: 10.1212/WNL.0000000000004234. Epub 2017 Jul 21.
• [4] 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.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [11] 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.
• [12] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [13] 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.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [16] BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin Cancer Res. 2014 Feb 15;20(4):912-25.
• [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.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.