Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT51UWUR)

• DOT Name: Phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA)
• Synonyms: EC 2.4.1.198; GlcNAc-PI synthesis protein; Phosphatidylinositol-glycan biosynthesis class A protein; PIG-A
• Gene Name: PIGA
• Related Disease:
  Epilepsy
  Multiple congenital anomalies-hypotonia-seizures syndrome 2
  Aplastic anemia
  Atypical hemolytic uremic syndrome
  Autoimmune disease
  Barrett esophagus
  Bone marrow failure syndrome
  Burkitt lymphoma
  Chromosomal disorder
  Early myoclonic encephalopathy
  Esophageal adenocarcinoma
  Gastroesophageal reflux disease
  Hematologic disease
  Inflammatory bowel disease
  Intellectual disability
  Plasma cell myeloma
  Plasma cell neoplasm
  Primary CD59 deficiency
  Simpson-Golabi-Behmel syndrome type 2
  Thrombotic microangiopathy
  Trichohepatoenteric syndrome
  Advanced cancer
  Hirschsprung disease
  Ferro-cerebro-cutaneous syndrome
  Malignant migrating partial seizures of infancy
  West syndrome
  Bone benign neoplasm
  Dental caries
  Myelodysplastic syndrome
  Myeloproliferative neoplasm
• UniProt ID: PIGA_HUMAN
• EC Number: 2.4.1.198
• Pfam ID: PF00534 ; PF08288
• Sequence:
  MACRGGAGNGHRASATLSRVSPGSLYTCRTRTHNICMVSDFFYPNMGGVESHIYQLSQCL
  IERGHKVIIVTHAYGNRKGIRYLTSGLKVYYLPLKVMYNQSTATTLFHSLPLLRYIFVRE
  RVTIIHSHSSFSAMAHDALFHAKTMGLQTVFTDHSLFGFADVSSVLTNKLLTVSLCDTNH
  IICVSYTSKENTVLRAALNPEIVSVIPNAVDPTDFTPDPFRRHDSITIVVVSRLVYRKGI
  DLLSGIIPELCQKYPDLNFIIGGEGPKRIILEEVRERYQLHDRVRLLGALEHKDVRNVLV
  QGHIFLNTSLTEAFCMAIVEAASCGLQVVSTRVGGIPEVLPENLIILCEPSVKSLCEGLE
  KAIFQLKSGTLPAPENIHNIVKTFYTWRNVAERTEKVYDRVSVEAVLPMDKRLDRLISHC
  GPVTGYIFALLAVFNFLFLIFLRWMTPDSIIDVAIDATGPRGAWTNNYSHSKRGGENNEI
  SETR
• Function: Catalytic subunit of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI biosynthesis.
• KEGG Pathway:
  Glycosylphosphatidylinositol (GPI)-anchor biosynthesis (hsa00563)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Synthesis of glycosylphosphatidylinositol (GPI) (R-HSA-162710)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Definitive	Genetic Variation	[1]
Multiple congenital anomalies-hypotonia-seizures syndrome 2	DIS93B6B	Definitive	X-linked recessive	[2]
Aplastic anemia	DISJRSC0	Strong	Genetic Variation	[3]
Atypical hemolytic uremic syndrome	DIS6FUDJ	Strong	Biomarker	[4]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[5]
Barrett esophagus	DIS416Y7	Strong	Genetic Variation	[6]
Bone marrow failure syndrome	DISVUY1J	Strong	Genetic Variation	[7]
Burkitt lymphoma	DIS9D5XU	Strong	Genetic Variation	[8]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[9]
Early myoclonic encephalopathy	DIS1YXVQ	Strong	Genetic Variation	[10]
Esophageal adenocarcinoma	DISODWFP	Strong	Genetic Variation	[6]
Gastroesophageal reflux disease	DISQ8G5S	Strong	Genetic Variation	[6]
Hematologic disease	DIS9XD9A	Strong	Genetic Variation	[7]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[11]
Intellectual disability	DISMBNXP	Strong	Biomarker	[12]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[13]
Plasma cell neoplasm	DIS2PJJM	Strong	Genetic Variation	[13]
Primary CD59 deficiency	DISQH167	Strong	Genetic Variation	[14]
Simpson-Golabi-Behmel syndrome type 2	DIS1YKCO	Strong	Genetic Variation	[12]
Thrombotic microangiopathy	DISLZ0VW	Strong	Biomarker	[4]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[15]
Advanced cancer	DISAT1Z9	moderate	Genetic Variation	[16]
Hirschsprung disease	DISUUSM1	moderate	Biomarker	[17]
Ferro-cerebro-cutaneous syndrome	DIS5HFLJ	Supportive	X-linked	[18]
Malignant migrating partial seizures of infancy	DISF2TRU	Supportive	Autosomal dominant	[19]
West syndrome	DISLIAU9	Supportive	Autosomal dominant	[20]
Bone benign neoplasm	DISEK84G	Limited	Genetic Variation	[21]
Dental caries	DISRBCMD	Limited	Genetic Variation	[22]
Myelodysplastic syndrome	DISYHNUI	Limited	Altered Expression	[23]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Biomarker	[24]

12 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 Phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA).	[25]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA).	[26]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA).	[27]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA).	[28]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA).	[29]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA).	[26]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the mutagenesis of Phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA).	[30]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA).	[31]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA).	[32]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA).	[35]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA).	[36]

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 decreases the methylation of Phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA).	[33]

References

• [1] A novel germline PIGA mutation causes early-onset epileptic encephalopathies in Chinese monozygotic twins.Brain Dev. 2018 Aug;40(7):596-600. doi: 10.1016/j.braindev.2018.02.009. Epub 2018 Mar 2.
• [2] The phenotype of a germline mutation in PIGA: the gene somatically mutated in paroxysmal nocturnal hemoglobinuria. Am J Hum Genet. 2012 Feb 10;90(2):295-300. doi: 10.1016/j.ajhg.2011.11.031. Epub 2012 Feb 2.
• [3] Advances in understanding the pathogenesis of acquired aplastic anaemia.Br J Haematol. 2018 Sep;182(6):758-776. doi: 10.1111/bjh.15443. Epub 2018 Jul 5.
• [4] Modified Ham test for atypical hemolytic uremic syndrome.Blood. 2015 Jun 4;125(23):3637-46. doi: 10.1182/blood-2015-02-629683. Epub 2015 Apr 10.
• [5] Cancer as an evolutionary process at the cell level: an epidemiological perspective.Carcinogenesis. 2003 Jan;24(1):1-6. doi: 10.1093/carcin/24.1.1.
• [6] Developing a blood-based gene mutation assay as a novel biomarker for oesophageal adenocarcinoma.Sci Rep. 2019 Mar 26;9(1):5168. doi: 10.1038/s41598-019-41490-w.
• [7] Circulating PIG-A mutant T lymphocytes in healthy adults and patients with bone marrow failure syndromes.Exp Hematol. 2001 Dec;29(12):1403-9. doi: 10.1016/s0301-472x(01)00746-9.
• [8] Silencing of genes required for glycosylphosphatidylinositol anchor biosynthesis in Burkitt lymphoma.Exp Hematol. 2009 Apr;37(4):423-434.e2. doi: 10.1016/j.exphem.2009.01.003.
• [9] No genotoxicity in rat blood cells upon 3- or 6-month inhalation exposure to CeO2 or BaSO4 nanomaterials.Mutagenesis. 2017 Jan;32(1):13-22. doi: 10.1093/mutage/gew005. Epub 2016 Feb 9.
• [10] PIGA mutations cause early-onset epileptic encephalopathies and distinctive features.Neurology. 2014 May 6;82(18):1587-96. doi: 10.1212/WNL.0000000000000389. Epub 2014 Apr 4.
• [11] The potential application of human PIG-A assay on azathioprine-treated inflammatory bowel disease patients.Environ Mol Mutagen. 2020 Apr;61(4):456-464. doi: 10.1002/em.22348. Epub 2019 Dec 6.
• [12] A recurrent germline mutation in the PIGA gene causes Simpson-Golabi-Behmel syndrome type 2.Am J Med Genet A. 2016 Feb;170A(2):392-402. doi: 10.1002/ajmg.a.37452. Epub 2015 Nov 6.
• [13] A quantitative analysis of genomic instability in lymphoid and plasma cell neoplasms based on the PIG-A gene.Mutat Res. 2010 Apr 1;686(1-2):1-8. doi: 10.1016/j.mrfmmm.2009.11.012. Epub 2010 Jan 8.
• [14] CD59 deficiency is associated with chronic hemolysis and childhood relapsing immune-mediated polyneuropathy. Blood. 2013 Jan 3;121(1):129-35. doi: 10.1182/blood-2012-07-441857. Epub 2012 Nov 13.
• [15] Detection of somatic mutations of the PIG-A gene in Brazilian patients with paroxysmal nocturnal hemoglobinuria.Braz J Med Biol Res. 2001 Jun;34(6):763-6. doi: 10.1590/s0100-879x2001000600010.
• [16] Monitoring genotoxicity in patients receiving chemotherapy for cancer: application of the PIG-A assay.Mutat Res Genet Toxicol Environ Mutagen. 2016 Sep 15;808:20-6. doi: 10.1016/j.mrgentox.2016.08.002. Epub 2016 Aug 10.
• [17] Phenotype-genotype correlations of PIGO deficiency with variable phenotypes from infantile lethality to mild learning difficulties.Hum Mutat. 2017 Jul;38(7):805-815. doi: 10.1002/humu.23219. Epub 2017 Apr 20.
• [18] A novel germline PIGA mutation in Ferro-Cerebro-Cutaneous syndrome: a neurodegenerative X-linked epileptic encephalopathy with systemic iron-overload. Am J Med Genet A. 2014 Jan;164A(1):17-28. doi: 10.1002/ajmg.a.36189. Epub 2013 Nov 20.
• [19] The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures. Ann Neurol. 2019 Dec;86(6):821-831. doi: 10.1002/ana.25619.
• [20] Early frameshift mutation in PIGA identified in a large XLID family without neonatal lethality. Hum Mutat. 2014 Mar;35(3):350-5. doi: 10.1002/humu.22498. Epub 2014 Jan 13.
• [21] Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH).Blood. 2006 Dec 15;108(13):4232-6. doi: 10.1182/blood-2006-05-025148. Epub 2006 Aug 29.
• [22] Paroxysmal nocturnal hemoglobinuria: insights from recent advances in molecular biology.Transfus Med Rev. 2001 Oct;15(4):255-67. doi: 10.1053/tmrv.2001.26958.
• [23] PIGN gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features.Oncotarget. 2017 May 2;8(18):29887-29905. doi: 10.18632/oncotarget.15136.
• [24] 3'UTR-truncated Hmga2 cDNA causes MPN-like hematopoiesis by conferring a clonal growth advantage at the level of HSC in mice.Blood. 2011 Jun 2;117(22):5860-9. doi: 10.1182/blood-2011-02-334425. Epub 2011 Apr 1.
• [25] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [26] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [27] 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.
• [28] 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.
• [29] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [30] Induction of clastogenesis and gene mutations by carbamazepine (at its therapeutically effective serum levels) in mammalian cells and the dependence on human CYP2B6 enzyme activity. Arch Toxicol. 2023 Jun;97(6):1753-1764. doi: 10.1007/s00204-023-03489-1. Epub 2023 Mar 30.
• [31] Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: microarray gene expression analyses. Mutat Res. 2005 Dec 11;591(1-2):198-211.
• [32] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [33] 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.
• [34] 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.
• [35] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [36] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.