Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSN7JUR)

• DOT Name: Alpha-crystallin A chain (CRYAA)
• Synonyms: Heat shock protein beta-4; HspB4
• Gene Name: CRYAA
• Related Disease:
  Cataract 9 multiple types
  Cataract - microcornea syndrome
  Early-onset anterior polar cataract
  Early-onset lamellar cataract
  Early-onset nuclear cataract
  Total early-onset cataract
• UniProt ID: CRYAA_HUMAN
• PDB ID: 6T1R
• Pfam ID: PF00525 ; PF00011
• Sequence:
  MDVTIQHPWFKRTLGPFYPSRLFDQFFGEGLFEYDLLPFLSSTISPYYRQSLFRTVLDSG
  ISEVRSDRDKFVIFLDVKHFSPEDLTVKVQDDFVEIHGKHNERQDDHGYISREFHRRYRL
  PSNVDQSALSCSLSADGMLTFCGPKIQTGLDATHAERAIPVSREEKPTSAPSS
• Function: Contributes to the transparency and refractive index of the lens. In its oxidized form (absence of intramolecular disulfide bond), acts as a chaperone, preventing aggregation of various proteins under a wide range of stress conditions. Required for the correct formation of lens intermediate filaments as part of a complex composed of BFSP1, BFSP2 and CRYAA.
• Tissue Specificity: Expressed in the eye lens (at protein level).
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cataract 9 multiple types	DIS9JQ8P	Definitive	Autosomal recessive	[1]
Cataract - microcornea syndrome	DISL51AQ	Supportive	Autosomal dominant	[2]
Early-onset anterior polar cataract	DISTOPIY	Supportive	Autosomal dominant	[3]
Early-onset lamellar cataract	DISR7WXX	Supportive	Autosomal dominant	[4]
Early-onset nuclear cataract	DISGIHUY	Supportive	Autosomal dominant	[5]
Total early-onset cataract	DISACMEZ	Supportive	Autosomal dominant	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Alpha-crystallin A chain (CRYAA) decreases the response to substance of Doxorubicin.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Alpha-crystallin A chain (CRYAA).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Alpha-crystallin A chain (CRYAA).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Alpha-crystallin A chain (CRYAA).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Alpha-crystallin A chain (CRYAA).	[8]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of Alpha-crystallin A chain (CRYAA).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Alpha-crystallin A chain (CRYAA).	[11]

References

• [1] A nonsense mutation (W9X) in CRYAA causes autosomal recessive cataract in an inbred Jewish Persian family. Invest Ophthalmol Vis Sci. 2000 Oct;41(11):3511-5.
• [2] Mutational screening of six genes in Chinese patients with congenital cataract and microcornea. Mol Vis. 2011;17:1508-13. Epub 2011 Jun 7.
• [3] Congenital anterior polar cataract associated with a missense mutation in the human alpha crystallin gene CRYAA. Mol Vis. 2011;17:2693-7. Epub 2011 Oct 15.
• [4] Identification of a novel oligomerization disrupting mutation in CRYA associated with congenital cataract in a South Australian family. Hum Mutat. 2013 Mar;34(3):435-8. doi: 10.1002/humu.22260. Epub 2013 Jan 17.
• [5] Mutation analysis of CRYAA, CRYGC, and CRYGD associated with autosomal dominant congenital cataract in Brazilian families. Mol Vis. 2009;15:793-800. Epub 2009 Apr 17.
• [6] Identification of a novel, putative cataract-causing allele in CRYAA (G98R) in an Indian family. Mol Vis. 2006 Jul 12;12:768-73.
• [7] 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.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] Sertraline induces endoplasmic reticulum stress in hepatic cells. Toxicology. 2014 Aug 1;322:78-88. doi: 10.1016/j.tox.2014.05.007. Epub 2014 May 24.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.