Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH9A75E)

• DOT Name: Post-GPI attachment to proteins factor 3 (PGAP3)
• Synonyms: COS16 homolog; hCOS16; Gene coamplified with ERBB2 protein; PER1-like domain-containing protein 1
• Gene Name: PGAP3
• Related Disease:
  Congenital disorder of glycosylation
  Hyperphosphatasia with intellectual disability syndrome 4
  Breast cancer
  Breast carcinoma
  Crohn disease
  Gastric cancer
  Inflammatory bowel disease
  Stomach cancer
  Toriello-Carey syndrome
  Bipolar disorder
  Intellectual disability
  Movement disorder
  Hyperphosphatasia-intellectual disability syndrome
  Gastric neoplasm
  Congenital nervous system disorder
• UniProt ID: PGAP3_HUMAN
• Pfam ID: PF04080
• Sequence:
  MAGLAARLVLLAGAAALASGSQGDREPVYRDCVLQCEEQNCSGGALNHFRSRQPIYMSLA
  GWTCRDDCKYECMWVTVGLYLQEGHKVPQFHGKWPFSRFLFFQEPASAVASFLNGLASLV
  MLCRYRTFVPASSPMYHTCVAFAWVSLNAWFWSTVFHTRDTDLTEKMDYFCASTVILHSI
  YLCCVRTVGLQHPAVVSAFRALLLLMLTVHVSYLSLIRFDYGYNLVANVAIGLVNVVWWL
  AWCLWNQRRLPHVRKCVVVVLLLQGLSLLELLDFPPLFWVLDAHAIWHISTIPVHVLFFS
  FLEDDSLYLLKESEDKFKLD
• Function: Involved in the lipid remodeling steps of GPI-anchor maturation. Lipid remodeling steps consist in the generation of 2 saturated fatty chains at the sn-2 position of GPI-anchors proteins. Required for phospholipase A2 activity that removes an acyl-chain at the sn-2 position of GPI-anchors during the remodeling of GPI.
• Tissue Specificity: Ubiquitously expressed, with highest levels in thyroid and placenta.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital disorder of glycosylation	DIS400QP	Definitive	Biomarker	[1]
Hyperphosphatasia with intellectual disability syndrome 4	DISX0K44	Definitive	Autosomal recessive	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Crohn disease	DIS2C5Q8	Strong	Altered Expression	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[4]
Stomach cancer	DISKIJSX	Strong	Biomarker	[3]
Toriello-Carey syndrome	DISZTO2J	Strong	Biomarker	[5]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[6]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[1]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[7]
Hyperphosphatasia-intellectual disability syndrome	DISQJ9HK	Supportive	Autosomal recessive	[1]
Gastric neoplasm	DISOKN4Y	Disputed	Biomarker	[8]
Congenital nervous system disorder	DIS2BIP8	Limited	Genetic Variation	[9]

5 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 Post-GPI attachment to proteins factor 3 (PGAP3).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Post-GPI attachment to proteins factor 3 (PGAP3).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Post-GPI attachment to proteins factor 3 (PGAP3).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Post-GPI attachment to proteins factor 3 (PGAP3).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Post-GPI attachment to proteins factor 3 (PGAP3).	[14]

References

• [1] Mutations in PGAP3 impair GPI-anchor maturation, causing a subtype of hyperphosphatasia with mental retardation. Am J Hum Genet. 2014 Feb 6;94(2):278-87. doi: 10.1016/j.ajhg.2013.12.012. Epub 2014 Jan 16.
• [2] 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.
• [3] Evolutionary recombination hotspot around GSDML-GSDM locus is closely linked to the oncogenomic recombination hotspot around the PPP1R1B-ERBB2-GRB7 amplicon.Int J Oncol. 2004 Apr;24(4):757-63.
• [4] Gene Expression-Genotype Analysis Implicates GSDMA, GSDMB, and LRRC3C as Contributors to Inflammatory Bowel Disease Susceptibility.Biomed Res Int. 2015;2015:834805. doi: 10.1155/2015/834805. Epub 2015 Sep 21.
• [5] Expanding the phenome and variome of skeletal dysplasia. Genet Med. 2018 Dec;20(12):1609-1616. doi: 10.1038/gim.2018.50. Epub 2018 Apr 5.
• [6] Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.Hum Mol Genet. 2016 Aug 1;25(15):3383-3394. doi: 10.1093/hmg/ddw181. Epub 2016 Jun 21.
• [7] PGAP3-related hyperphosphatasia with mental retardation syndrome: Report of 10 new patients and a homozygous founder mutation.Clin Genet. 2018 Jan;93(1):84-91. doi: 10.1111/cge.13033. Epub 2017 Aug 4.
• [8] MGC9753 gene, located within PPP1R1B-STARD3-ERBB2-GRB7 amplicon on human chromosome 17q12, encodes the seven-transmembrane receptor with extracellular six-cystein domain.Int J Oncol. 2003 Jun;22(6):1369-74.
• [9] Hyperphosphatasia with mental retardation syndrome type 4 In two siblings-expanding the phenotypic and mutational spectrum.Eur J Med Genet. 2019 Jun;62(6):103535. doi: 10.1016/j.ejmg.2018.09.002. Epub 2018 Sep 11.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.