Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFOWNH2)

• DOT Name: Keratin, type I cytoskeletal 12 (KRT12)
• Synonyms: Cytokeratin-12; CK-12; Keratin-12; K12
• Gene Name: KRT12
• Related Disease:
  Corneal dystrophy, Meesmann, 1
  Aniridia
  Macular corneal dystrophy
  Corneal disease
  Keratoconus
  Meesmann corneal dystrophy
  Corneal dystrophy
  Sickle-cell anaemia
• UniProt ID: K1C12_HUMAN
• Pfam ID: PF00038
• Sequence:
  MDLSNNTMSLSVRTPGLSRRLSSQSVIGRPRGMSASSVGSGYGGSAFGFGASCGGGFSAA
  SMFGSSSGFGGGSGSSMAGGLGAGYGRALGGGSFGGLGMGFGGSPGGGSLGILSGNDGGL
  LSGSEKETMQNLNDRLASYLDKVRALEEANTELENKIREWYETRGTGTADASQSDYSKYY
  PLIEDLRNKIISASIGNAQLLLQIDNARLAAEDFRMKYENELALRQGVEADINGLRRVLD
  ELTLTRTDLEMQIESLNEELAYMKKNHEDELQSFRVGGPGEVSVEMDAAPGVDLTRLLND
  MRAQYETIAEQNRKDAEAWFIEKSGELRKEISTNTEQLQSSKSEVTDLRRAFQNLEIELQ
  SQLAMKKSLEDSLAEAEGDYCAQLSQVQQLISNLEAQLLQVRADAERQNVDHQRLLNVKA
  RLELEIETYRRLLDGEAQGDGLEESLFVTDSKSQAQSTDSSKDPTKTRKIKTVVQEMVNG
  EVVSSQVQEIEELM
• Function: Involved in corneal epithelium organization, integrity and corneal keratin expression.
• Tissue Specificity: Expressed in the corneal epithelium (at protein level).
• KEGG Pathway:
  Estrogen sig.ling pathway (hsa04915)
  Staphylococcus aureus infection (hsa05150)
• Reactome Pathway:
  Formation of the cornified envelope (R-HSA-6809371)
  Keratinization (R-HSA-6805567)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Corneal dystrophy, Meesmann, 1	DIST4WI6	Definitive	Autosomal dominant	[1]
Aniridia	DIS1P333	Strong	Altered Expression	[2]
Macular corneal dystrophy	DISOLD0H	Strong	Genetic Variation	[3]
Corneal disease	DISTUIM1	moderate	Biomarker	[4]
Keratoconus	DISOONXH	moderate	Genetic Variation	[5]
Meesmann corneal dystrophy	DISJFWTC	Supportive	Autosomal dominant	[6]
Corneal dystrophy	DISRDPA6	Limited	Genetic Variation	[7]
Sickle-cell anaemia	DIS5YNZB	Limited	Biomarker	[8]

2 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 Keratin, type I cytoskeletal 12 (KRT12).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Keratin, type I cytoskeletal 12 (KRT12).	[12]

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 Keratin, type I cytoskeletal 12 (KRT12).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Keratin, type I cytoskeletal 12 (KRT12).	[11]

References

• [1] Isolation and chromosomal localization of a cornea-specific human keratin 12 gene and detection of four mutations in Meesmann corneal epithelial dystrophy. Am J Hum Genet. 1997 Dec;61(6):1268-75. doi: 10.1086/301650.
• [2] Human aniridia limbal epithelial cells lack expression of keratins K3 and K12.Exp Eye Res. 2018 Feb;167:100-109. doi: 10.1016/j.exer.2017.11.005. Epub 2017 Nov 21.
• [3] Novel mutations in the helix termination motif of keratin 3 and keratin 12 in 2 Taiwanese families with Meesmann corneal dystrophy. Cornea. 2005 Nov;24(8):928-32. doi: 10.1097/01.ico.0000159732.29930.26.
• [4] Proteome profiling of corneal epithelium and identification of marker proteins for keratoconus, a pilot study.Exp Eye Res. 2006 Feb;82(2):201-9. doi: 10.1016/j.exer.2005.06.009. Epub 2005 Aug 3.
• [5] Mutation analysis of TGFBI and KRT12 in a case of concomitant keratoconus and granular corneal dystrophy.Graefes Arch Clin Exp Ophthalmol. 2017 Sep;255(9):1779-1786. doi: 10.1007/s00417-017-3699-5. Epub 2017 May 31.
• [6] Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann's corneal dystrophy. Nat Genet. 1997 Jun;16(2):184-7. doi: 10.1038/ng0697-184.
• [7] Identification of a novel mutation in the cornea specific keratin 12 gene causing Meesmann's corneal dystrophy in a German family.Mol Vis. 2010 May 29;16:954-60.
• [8] Harnessing the potential of gene editing technology using CRISPR in inflammatory bowel disease.World J Gastroenterol. 2019 May 14;25(18):2177-2187. doi: 10.3748/wjg.v25.i18.2177.
• [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] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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.