Details of Drug Off-Target (DOT)

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

• DOT Name: GPI ethanolamine phosphate transferase 1 (PIGN)
• Synonyms: EC 2.-.-.-; MCD4 homolog; Phosphatidylinositol-glycan biosynthesis class N protein; PIG-N
• Gene Name: PIGN
• Related Disease:
  Multiple congenital anomalies-hypotonia-seizures syndrome 1
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Colorectal carcinoma
  Congenital diaphragmatic hernia
  Epilepsy
  Intellectual disability
  Lung adenocarcinoma
  Myelodysplastic syndrome
  Paroxysmal dyskinesia
  Pulmonary fibrosis
  Staphylococcus infection
  Bone Paget disease
  Movement disorder
  Paget's disease
  Fryns syndrome
• UniProt ID: PIGN_HUMAN
• EC Number: 2.-.-.-
• Pfam ID: PF01663 ; PF04987
• Sequence:
  MLLFFTLGLLIHFVFFASIFDIYFTSPLVHGMTPQFTPLPPPARRLVLFVADGLRADALY
  ELDENGNSRAPFIRNIIMHEGSWGISHTRVPTESRPGHVALIAGFYEDVSAVAKGWKENP
  VEFDSLFNESKYTWSWGSPDILPMFAKGASGDHVYTYSYDAKREDFGAQDATKLDTWVFD
  NVKDFFHHARNNQSLFSKINEEKIVFFLHLLGIDTNGHAHRPSSRDYKHNIKKVDDGVKE
  IVSMFNHFYGNDGKTTFIFTSDHGMTDWGSHGAGHPSETLTPLVTWGAGIKYPQRVSAQQ
  FDDAFLKEWRLENWKRLDVNQADIAPLMTSLIGVPFPLNSVGILPVDYLNNTDLFKAESM
  FTNAVQILEQFKVKMTQKKEVTLPFLFTPFKLLSDSKQFNILRKARSYIKHRKFDEVVSL
  CKELIHLALKGLSYYHTYDRFFLGVNVVIGFVGWISYASLLIIKSHSNLIKGVSKEVKKP
  SHLLPCSFVAIGILVAFFLLIQACPWTYYVYGLLPLPIWYAVLREFQVIQDLVVSVLTYP
  LSHFVGYLLAFTLGIEVLVLSFFYRYMLTAGLTAFAAWPFLTRLWTRAKMTSLSWTFFSL
  LLAVFPLMPVVGRKPDISLVMGAGLLVLLLSLCVVTSLMKRKDSFIKEELLVHLLQVLST
  VLSMYVVYSTQSSLLRKQGLPLMNQIISWATLASSLVVPLLSSPVLFQRLFSILLSLMST
  YLLLSTGYEALFPLVLSCLMFVWINIEQETLQQSGVCCKQKLTSIQFSYNTDITQFRQLY
  LDDIRRAFFLVFFLVTAFFGTGNIASINSFDLASVYCFLTVFSPFMMGALMMWKILIPFV
  LVMCAFEAVQLTTQLSSKSLFLIVLVISDIMALHFFFLVKDYGSWLDIGTSISHYVIVMS
  MTIFLVFLNGLAQLLTTKKLRLCGKPKSHFM
• Function: Ethanolamine phosphate transferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers ethanolamine phosphate to the first alpha-1,4-linked mannose of the glycosylphosphatidylinositol precursor of GPI-anchor. May act as suppressor of replication stress and chromosome missegregation.
• 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

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple congenital anomalies-hypotonia-seizures syndrome 1	DISDQTL8	Definitive	Autosomal recessive	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Genetic Variation	[4]
Epilepsy	DISBB28L	Strong	Genetic Variation	[5]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[5]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[6]
Myelodysplastic syndrome	DISYHNUI	Strong	Altered Expression	[2]
Paroxysmal dyskinesia	DIS5XVXE	Strong	Genetic Variation	[7]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[8]
Staphylococcus infection	DISY8WGS	Strong	Biomarker	[9]
Bone Paget disease	DISIPS4V	moderate	Genetic Variation	[10]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[11]
Paget's disease	DISO3MC0	moderate	Genetic Variation	[10]
Fryns syndrome	DISGBIQY	Supportive	Autosomal recessive	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of GPI ethanolamine phosphate transferase 1 (PIGN).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of GPI ethanolamine phosphate transferase 1 (PIGN).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of GPI ethanolamine phosphate transferase 1 (PIGN).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GPI ethanolamine phosphate transferase 1 (PIGN).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of GPI ethanolamine phosphate transferase 1 (PIGN).	[17]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of GPI ethanolamine phosphate transferase 1 (PIGN).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of GPI ethanolamine phosphate transferase 1 (PIGN).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of GPI ethanolamine phosphate transferase 1 (PIGN).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of GPI ethanolamine phosphate transferase 1 (PIGN).	[21]

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] 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.
• [3] Replication stress links structural and numerical cancer chromosomal instability.Nature. 2013 Feb 28;494(7438):492-496. doi: 10.1038/nature11935.
• [4] Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Runion Island, in patients with Fryns syndrome.Eur J Hum Genet. 2018 Mar;26(3):340-349. doi: 10.1038/s41431-017-0087-x. Epub 2018 Jan 12.
• [5] Hypotonia and intellectual disability without dysmorphic features in a patient with PIGN-related disease.BMC Med Genet. 2017 Nov 2;18(1):124. doi: 10.1186/s12881-017-0481-9.
• [6] c-Myc targeted regulators of cell metabolism in a transgenic mouse model of papillary lung adenocarcinoma.Oncotarget. 2016 Oct 4;7(40):65514-65539. doi: 10.18632/oncotarget.11804.
• [7] A homozygous PIGN missense mutation in Soft-Coated Wheaten Terriers with a canine paroxysmal dyskinesia.Neurogenetics. 2017 Jan;18(1):39-47. doi: 10.1007/s10048-016-0502-4. Epub 2016 Nov 28.
• [8] Anti-inflammatory and anti-fibrotic effects of intravenous adipose-derived stem cell transplantation in a mouse model of bleomycin-induced interstitial pneumonia.Sci Rep. 2017 Nov 6;7(1):14608. doi: 10.1038/s41598-017-15022-3.
• [9] IgA-dominant extracapillary proliferative glomerulonephritis following Escherichia coli sepsis in a renal transplant recipient.Transpl Infect Dis. 2018 Oct;20(5):e12927. doi: 10.1111/tid.12927. Epub 2018 Jun 15.
• [10] Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone.Nat Genet. 2010 Jun;42(6):520-4. doi: 10.1038/ng.562. Epub 2010 May 2.
• [11] Congenital disorder of glycosylphosphatidylinositol (GPI)-anchor biosynthesis--The phenotype of two patients with novel mutations in the PIGN and PGAP2 genes.Eur J Paediatr Neurol. 2016 May;20(3):462-73. doi: 10.1016/j.ejpn.2016.01.007. Epub 2016 Feb 4.
• [12] Fryns Syndrome Associated with Recessive Mutations in PIGN in two Separate Families. Hum Mutat. 2016 Jul;37(7):695-702. doi: 10.1002/humu.22994. Epub 2016 May 6.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] 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.
• [15] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] 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.
• [18] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [19] 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.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.