Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMCFF0K)

• DOT Name: Phosphatidylinositol N-acetylglucosaminyltransferase subunit H (PIGH)
• Synonyms: Phosphatidylinositol-glycan biosynthesis class H protein; PIG-H
• Gene Name: PIGH
• Related Disease:
  Advanced cancer
  Autism
  Epilepsy
  Glycosylphosphatidylinositol biosynthesis defect 17
  Isolated congenital microcephaly
  Neoplasm
• UniProt ID: PIGH_HUMAN
• Pfam ID: PF10181
• Sequence:
  MEDERSFSDICGGRLALQRRYYSPSCREFCLSCPRLSLRSLTAVTCTVWLAAYGLFTLCE
  NSMILSAAIFITLLGLLGYLHFVKIDQETLLIIDSLGIQMTSSYASGKESTTFIEMGKVK
  DIVINEAIYMQKVIYYLCILLKDPVEPHGISQVVPVFQSAKPRLDCLIEVYRSCQEILAH
  QKATSTSP
• Function: Part 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

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Epilepsy	DISBB28L	Strong	Genetic Variation	[3]
Glycosylphosphatidylinositol biosynthesis defect 17	DISBQX3C	Strong	Autosomal recessive	[4]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]

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 Phosphatidylinositol N-acetylglucosaminyltransferase subunit H (PIGH).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit H (PIGH).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit H (PIGH).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit H (PIGH).	[8]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit H (PIGH).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit H (PIGH).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit H (PIGH).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit H (PIGH).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit H (PIGH).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Phosphatidylinositol N-acetylglucosaminyltransferase subunit H (PIGH).	[14]

References

• [1] Biomineralized Gd(2) O(3) @HSA Nanoparticles as a Versatile Platform for Dual-Modal Imaging and Chemo-Phototherapy-Synergized Tumor Ablation.Adv Healthc Mater. 2019 Dec;8(24):e1901005. doi: 10.1002/adhm.201901005. Epub 2019 Nov 18.
• [2] A PIGH mutation leading to GPI deficiency is associated with developmental delay and autism. Hum Mutat. 2018 Jun;39(6):827-829. doi: 10.1002/humu.23426. Epub 2018 Apr 26.
• [3] A homozygous variant disrupting the PIGH start-codon is associated with developmental delay, epilepsy, and microcephaly. Hum Mutat. 2018 Jun;39(6):822-826. doi: 10.1002/humu.23420. Epub 2018 Mar 30.
• [4] PIGH deficiency can be associated with severe neurodevelopmental and skeletal manifestations. Clin Genet. 2021 Feb;99(2):313-317. doi: 10.1111/cge.13877. Epub 2020 Nov 27.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] 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.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [9] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] 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.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.