Details of Drug Off-Target (DOT)

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

• DOT Name: Chorion-specific transcription factor GCMb (GCM2)
• Synonyms: hGCMb; GCM motif protein 2; Glial cells missing homolog 2
• Gene Name: GCM2
• Related Disease:
  Hypercalcaemia
  Adenoma
  Breast cancer
  Breast carcinoma
  Hyperparathyroidism
  Hypoparathyroidism, familial isolated, 2
  Insulinoma
  Multiple endocrine neoplasia type 1
  Neoplasm
  Pancreatic neuroendocrine tumor
  Hypoparathyroidism-deafness-renal disease syndrome
  Familial isolated hyperparathyroidism
  Familial isolated hypoparathyroidism due to agenesis of parathyroid gland
  Hyperparathyroidism 4
  Hypoparathyroidism
  Neuroendocrine neoplasm
  Parathyroid gland carcinoma
• UniProt ID: GCM2_HUMAN
• Pfam ID: PF03615
• Sequence:
  MPAAAVQEAVGVCSYGMQLSWDINDPQMPQELALFDQFREWPDGYVRFIYSSDEKKAQRH
  LSGWAMRNTNNHNGHILKKSCLGVVVCTQACTLPDGSRLQLRPAICDKARLKQQKKACPN
  CHSALELIPCRGHSGYPVTNFWRLDGNAIFFQAKGVHDHPRPESKSETEARRSAIKRQMA
  SFYQPQKKRIRESEAEENQDSSGHFSNIPPLENPEDFDIVTETSFPIPGQPCPSFPKSDV
  YKATCDLATFQGDKMPPFQKYSSPRIYLPRPPCSYELANPGYTNSSPYPTLYKDSTSIPN
  DTDWVHLNTLQCNVNSYSSYERSFDFTNKQHGWKPALGKPSLVERTNHGQFQAMATRPYY
  NPELPCRYLTTPPPGAPALQTVITTTTKVSYQAYQPPAMKYSDSVREVKSLSSCNYAPED
  TGMSVYPEPWGPPVTVTRAASPSGPPPMKIAGDCRAIRPTVAIPHEPVSSRTDEAETWDV
  CLSGLGSAVSYSDRVGPFFTYNNEDF
• Function: Transcription factor that binds specific sequences on gene promoters and activate their transcription. Through the regulation of gene transcription, may play a role in parathyroid gland development.
• KEGG Pathway: Parathyroid hormone synthesis, secretion and action (hsa04928)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypercalcaemia	DISKQ2K7	Definitive	Genetic Variation	[1]
Adenoma	DIS78ZEV	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Hyperparathyroidism	DIS4FVAT	Strong	Genetic Variation	[4]
Hypoparathyroidism, familial isolated, 2	DISQVMMW	Strong	Autosomal recessive	[5]
Insulinoma	DISIU1JS	Strong	Biomarker	[3]
Multiple endocrine neoplasia type 1	DIS0RJRK	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Pancreatic neuroendocrine tumor	DISDMPU0	Strong	Biomarker	[3]
Hypoparathyroidism-deafness-renal disease syndrome	DISRCBP9	moderate	Biomarker	[6]
Familial isolated hyperparathyroidism	DISC2Y84	Supportive	Autosomal dominant	[7]
Familial isolated hypoparathyroidism due to agenesis of parathyroid gland	DISPDS1V	Supportive	Autosomal recessive	[8]
Hyperparathyroidism 4	DIS5XBN5	Limited	Unknown	[7]
Hypoparathyroidism	DISICS0V	Limited	Biomarker	[9]
Neuroendocrine neoplasm	DISNPLOO	Limited	Genetic Variation	[10]
Parathyroid gland carcinoma	DISEER2W	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Chorion-specific transcription factor GCMb (GCM2).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Chorion-specific transcription factor GCMb (GCM2).	[14]

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 increases the methylation of Chorion-specific transcription factor GCMb (GCM2).	[13]

References

• [1] New Concepts About Familial Isolated Hyperparathyroidism.J Clin Endocrinol Metab. 2019 Sep 1;104(9):4058-4066. doi: 10.1210/jc.2018-02789.
• [2] Expression of GCMB by intrathymic parathyroid hormone-secreting adenomas indicates their parathyroid cell origin.J Clin Endocrinol Metab. 2004 Jan;89(1):8-12. doi: 10.1210/jc.2003-030733.
• [3] Recent Topics Around Multiple Endocrine Neoplasia Type 1.J Clin Endocrinol Metab. 2018 Apr 1;103(4):1296-1301. doi: 10.1210/jc.2017-02340.
• [4] Specifying the molecular pattern of sporadic parathyroid tumorigenesis-The Y282D variant of the GCM2 gene.Biomed Pharmacother. 2017 Aug;92:843-848. doi: 10.1016/j.biopha.2017.05.028. Epub 2017 Jun 9.
• [5] Identification and characterization of novel parathyroid-specific transcription factor Glial Cells Missing Homolog B (GCMB) mutations in eight families with autosomal recessive hypoparathyroidism. Hum Mol Genet. 2010 May 15;19(10):2028-38. doi: 10.1093/hmg/ddq084. Epub 2010 Feb 27.
• [6] Gata3 cooperates with Gcm2 and MafB to activate parathyroid hormone gene expression by interacting with SP1.Mol Cell Endocrinol. 2015 Aug 15;411:113-20. doi: 10.1016/j.mce.2015.04.018. Epub 2015 Apr 24.
• [7] GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism. Am J Hum Genet. 2016 Nov 3;99(5):1034-1044. doi: 10.1016/j.ajhg.2016.08.018. Epub 2016 Oct 13.
• [8] Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB. J Clin Invest. 2001 Oct;108(8):1215-20. doi: 10.1172/JCI13180.
• [9] Idiopathic hypoparathyroidism with extensive intracranial calcification in children: First report from Saudi Arabia.Medicine (Baltimore). 2017 Apr;96(16):e6347. doi: 10.1097/MD.0000000000006347.
• [10] Should the GCM2 gene be tested when screening for familial primary hyperparathyroidism?.Eur J Endocrinol. 2020 Jan;182(1):57-65. doi: 10.1530/EJE-19-0641.
• [11] Familial isolated primary hyperparathyroidism associated with germline GCM2 mutations is more aggressive and has a lesser rate of biochemical cure.Surgery. 2018 Jan;163(1):31-34. doi: 10.1016/j.surg.2017.04.027. Epub 2017 Nov 3.
• [12] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] 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.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.