Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5Z5IW8)

• DOT Name: Pseudokinase FAM20A (FAM20A)
• Gene Name: FAM20A
• Related Disease:
  Amelogenesis imperfecta type 1G
  Amelogenesis imperfecta type 1
  Juvenile idiopathic arthritis
  Nephrocalcinosis
  Nephropathy
  Periodontal disease
  Periodontitis
  Systemic sclerosis
  Tooth agenesis
  Amelogenesis imperfecta
  Exanthem
• UniProt ID: FA20A_HUMAN
• PDB ID: 5WRR; 5WRS; 5YH2; 5YH3
• Pfam ID: PF06702
• Sequence:
  MPGLRRDRLLTLLLLGALLSADLYFHLWPQVQRQLRPRERPRGCPCTGRASSLARDSAAA
  ASDPGTIVHNFSRTEPRTEPAGGSHSGSSSKLQALFAHPLYNVPEEPPLLGAEDSLLASQ
  EALRYYRRKVARWNRRHKMYREQMNLTSLDPPLQLRLEASWVQFHLGINRHGLYSRSSPV
  VSKLLQDMRHFPTISADYSQDEKALLGACDCTQIVKPSGVHLKLVLRFSDFGKAMFKPMR
  QQRDEETPVDFFYFIDFQRHNAEIAAFHLDRILDFRRVPPTVGRIVNVTKEILEVTKNEI
  LQSVFFVSPASNVCFFAKCPYMCKTEYAVCGNPHLLEGSLSAFLPSLNLAPRLSVPNPWI
  RSYTLAGKEEWEVNPLYCDTVKQIYPYNNSQRLLNVIDMAIFDFLIGNMDRHHYEMFTKF
  GDDGFLIHLDNARGFGRHSHDEISILSPLSQCCMIKKKTLLHLQLLAQADYRLSDVMRES
  LLEDQLSPVLTEPHLLALDRRLQTILRTVEGCIVAHGQQSVIVDGPVEQLAPDSGQANLT
  S
• Function: Pseudokinase that acts as an allosteric activator of the Golgi serine/threonine protein kinase FAM20C and is involved in biomineralization of teeth. Forms a complex with FAM20C and increases the ability of FAM20C to phosphorylate the proteins that form the 'matrix' that guides the deposition of the enamel minerals.
• Tissue Specificity: Highly expressed in lung and liver. Intermediate levels in thymus and ovary.
• Reactome Pathway:
  Post-translational protein phosphorylation (R-HSA-8957275)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amelogenesis imperfecta type 1G	DISS8U5Q	Definitive	Autosomal recessive	[1]
Amelogenesis imperfecta type 1	DISVEG5A	Strong	Genetic Variation	[2]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[3]
Nephrocalcinosis	DIS5ZVJP	Strong	Genetic Variation	[4]
Nephropathy	DISXWP4P	Strong	Genetic Variation	[4]
Periodontal disease	DISJQHVN	Strong	Genetic Variation	[5]
Periodontitis	DISI9JOI	Strong	Genetic Variation	[5]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[6]
Tooth agenesis	DIS1PWC7	Strong	Genetic Variation	[5]
Amelogenesis imperfecta	DISGYR9E	Limited	Genetic Variation	[7]
Exanthem	DISAFOQN	Limited	Biomarker	[8]

13 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 Pseudokinase FAM20A (FAM20A).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Pseudokinase FAM20A (FAM20A).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Pseudokinase FAM20A (FAM20A).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pseudokinase FAM20A (FAM20A).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Pseudokinase FAM20A (FAM20A).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Pseudokinase FAM20A (FAM20A).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Pseudokinase FAM20A (FAM20A).	[15]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Pseudokinase FAM20A (FAM20A).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Pseudokinase FAM20A (FAM20A).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Pseudokinase FAM20A (FAM20A).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Pseudokinase FAM20A (FAM20A).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Pseudokinase FAM20A (FAM20A).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Pseudokinase FAM20A (FAM20A).	[21]

References

• [1] Whole-Exome sequencing identifies FAM20A mutations as a cause of amelogenesis imperfecta and gingival hyperplasia syndrome. Am J Hum Genet. 2011 May 13;88(5):616-20. doi: 10.1016/j.ajhg.2011.04.005. Epub 2011 May 5.
• [2] Novel FAM20A mutations in hypoplastic amelogenesis imperfecta. Hum Mutat. 2012 Jan;33(1):91-4. doi: 10.1002/humu.21621. Epub 2011 Oct 31.
• [3] Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets.Arthritis Rheum. 2009 Jul;60(7):2113-23. doi: 10.1002/art.24534.
• [4] Nephrocalcinosis in Amelogenesis Imperfecta Caused by the FAM20A Mutation.Nephron. 2018;139(2):189-196. doi: 10.1159/000486607. Epub 2018 Feb 13.
• [5] Periodontal disease and FAM20A mutations.J Hum Genet. 2017 Jul;62(7):679-686. doi: 10.1038/jhg.2017.26. Epub 2017 Mar 16.
• [6] A potential new approach for treating systemic sclerosis: Dedifferentiation of SSc fibroblasts and change in the microenvironment by blocking store-operated Ca2+ entry.PLoS One. 2019 Mar 14;14(3):e0213400. doi: 10.1371/journal.pone.0213400. eCollection 2019.
• [7] FAM20A is essential for amelogenesis, but is dispensable for dentinogenesis.J Mol Histol. 2019 Dec;50(6):581-591. doi: 10.1007/s10735-019-09851-x. Epub 2019 Oct 30.
• [8] FAM20A mutations associated with enamel renal syndrome.J Dent Res. 2014 Jan;93(1):42-8. doi: 10.1177/0022034513512653. Epub 2013 Nov 6.
• [9] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells. Toxicol Appl Pharmacol. 2017 Sep 15;331:154-163.
• [15] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [16] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [17] 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.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] Transcriptomic?pathway?and?benchmark dose analysis of Bisphenol A, Bisphenol S, Bisphenol F, and 3,3',5,5'-Tetrabromobisphenol A in H9 human embryonic stem cells. Toxicol In Vitro. 2021 Apr;72:105097. doi: 10.1016/j.tiv.2021.105097. Epub 2021 Jan 18.