Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5V9PIR)

• DOT Name: Alpha-1,2-mannosyltransferase ALG9 (ALG9)
• Synonyms: EC 2.4.1.259; EC 2.4.1.261; Asparagine-linked glycosylation protein 9 homolog; Disrupted in bipolar disorder protein 1; Dol-P-Man:Man(6)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase; Dol-P-Man:Man(8)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase
• Gene Name: ALG9
• Related Disease:
  ALG9-associated autosomal dominant polycystic kidney disease
  ALG9-congenital disorder of glycosylation
  Autosomal dominant polycystic liver disease
  Cardiovascular disease
  Congenital disorder of glycosylation
  Galactosemia
  Neuroendocrine neoplasm
  Non-immune hydrops fetalis
  Osteochondrodysplasia
  Polycystic kidney disease
  Schizophrenia
  Skeletal dysplasia
  Tourette syndrome
  Autosomal dominant polycystic kidney disease
  Gillessen-Kaesbach-Nishimura syndrome
  Psychotic disorder
• UniProt ID: ALG9_HUMAN
• EC Number: 2.4.1.259; 2.4.1.261
• Pfam ID: PF03901
• Sequence:
  MASRGARQRLKGSGASSGDTAPAADKLRELLGSREAGGAEHRTELSGNKAGQVWAPEGST
  AFKCLLSARLCAALLSNISDCDETFNYWEPTHYLIYGEGFQTWEYSPAYAIRSYAYLLLH
  AWPAAFHARILQTNKILVFYFLRCLLAFVSCICELYFYKAVCKKFGLHVSRMMLAFLVLS
  TGMFCSSSAFLPSSFCMYTTLIAMTGWYMDKTSIAVLGVAAGAILGWPFSAALGLPIAFD
  LLVMKHRWKSFFHWSLMALILFLVPVVVIDSYYYGKLVIAPLNIVLYNVFTPHGPDLYGT
  EPWYFYLINGFLNFNVAFALALLVLPLTSLMEYLLQRFHVQNLGHPYWLTLAPMYIWFII
  FFIQPHKEERFLFPVYPLICLCGAVALSALQKCYHFVFQRYRLEHYTVTSNWLALGTVFL
  FGLLSFSRSVALFRGYHGPLDLYPEFYRIATDPTIHTVPEGRPVNVCVGKEWYRFPSSFL
  LPDNWQLQFIPSEFRGQLPKPFAEGPLATRIVPTDMNDQNLEEPSRYIDISKCHYLVDLD
  TMRETPREPKYSSNKEEWISLAYRPFLDASRSSKLLRAFYVPFLSDQYTVYVNYTILKPR
  KAKQIRKKSGG
• Function: Catalyzes the transfer of mannose from Dol-P-Man to lipid-linked oligosaccharides.
• Tissue Specificity: Ubiquitously expressed; with highest levels in heart, liver and pancreas.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Various types of N-glycan biosynthesis (hsa00513)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective ALG9 causes CDG-1l (R-HSA-4720454)
  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

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
ALG9-associated autosomal dominant polycystic kidney disease	DISMIOMG	Definitive	Autosomal dominant	[1]
ALG9-congenital disorder of glycosylation	DISTGKN8	Strong	Autosomal recessive	[2]
Autosomal dominant polycystic liver disease	DISJS005	Strong	Biomarker	[3]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[4]
Congenital disorder of glycosylation	DIS400QP	Strong	Genetic Variation	[5]
Galactosemia	DIS6V2Q3	Strong	Altered Expression	[6]
Neuroendocrine neoplasm	DISNPLOO	Strong	Genetic Variation	[7]
Non-immune hydrops fetalis	DISPUY8C	Strong	Genetic Variation	[5]
Osteochondrodysplasia	DIS9SPWW	Strong	Genetic Variation	[8]
Polycystic kidney disease	DISWS3UY	Strong	CausalMutation	[8]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[9]
Skeletal dysplasia	DIS5Z8U6	Strong	Genetic Variation	[8]
Tourette syndrome	DISX9D54	Strong	Genetic Variation	[9]
Autosomal dominant polycystic kidney disease	DISBHWUI	Moderate	Autosomal dominant	[10]
Gillessen-Kaesbach-Nishimura syndrome	DIS16UQ4	Moderate	Autosomal recessive	[11]
Psychotic disorder	DIS4UQOT	Limited	Genetic Variation	[12]

6 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 Alpha-1,2-mannosyltransferase ALG9 (ALG9).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Alpha-1,2-mannosyltransferase ALG9 (ALG9).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Alpha-1,2-mannosyltransferase ALG9 (ALG9).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Alpha-1,2-mannosyltransferase ALG9 (ALG9).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Alpha-1,2-mannosyltransferase ALG9 (ALG9).	[19]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Alpha-1,2-mannosyltransferase ALG9 (ALG9).	[20]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Alpha-1,2-mannosyltransferase ALG9 (ALG9).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Alpha-1,2-mannosyltransferase ALG9 (ALG9).	[18]

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] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] ALG9 Mutation Carriers Develop Kidney and Liver Cysts. J Am Soc Nephrol. 2019 Nov;30(11):2091-2102. doi: 10.1681/ASN.2019030298. Epub 2019 Aug 8.
• [4] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [5] Nonimmune hydrops fetalis and congenital disorders of glycosylation: A systematic literature review.J Inherit Metab Dis. 2020 Mar;43(2):223-233. doi: 10.1002/jimd.12162. Epub 2019 Nov 8.
• [6] Classical galactosaemia: novel insights in IgG N-glycosylation and N-glycan biosynthesis.Eur J Hum Genet. 2016 Jul;24(7):976-84. doi: 10.1038/ejhg.2015.254. Epub 2016 Jan 6.
• [7] Predicting neuroendocrine tumor (carcinoid) neoplasia using gene expression profiling and supervised machine learning.Cancer. 2009 Apr 15;115(8):1638-50. doi: 10.1002/cncr.24180.
• [8] A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9.Eur J Hum Genet. 2016 Feb;24(2):198-207. doi: 10.1038/ejhg.2015.91. Epub 2015 May 13.
• [9] A mannosyltransferase gene at 11q23 is disrupted by a translocation breakpoint that co-segregates with bipolar affective disorder in a small family.Neurogenetics. 2002 Mar;4(1):43-53. doi: 10.1007/s10048-001-0129-x.
• [10] 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.
• [11] 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.
• [12] A hypothesis for how chromosome 11 translocations cause psychiatric disorders.Genetics. 2007 Oct;177(2):1259-62. doi: 10.1534/genetics.107.077875. Epub 2007 Aug 24.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] 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.
• [15] 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.
• [16] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [17] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [18] 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.
• [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] Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents. Food Chem Toxicol. 2017 Oct;108(Pt A):30-42.