Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4JMRN6)

• DOT Name: Keratin, type I cytoskeletal 25 (KRT25)
• Synonyms: Cytokeratin-25; CK-25; Keratin-25; K25; Keratin-25A; K25A; Type I inner root sheath-specific keratin-K25irs1
• Gene Name: KRT25
• Related Disease:
  Hypercholesterolemia, familial, 4
  Hypotrichosis 8
  Wooly hair, autosomal recessive 3
  Isolated familial wooly hair disorder
  Hypotrichosis
• UniProt ID: K1C25_HUMAN
• Pfam ID: PF00038
• Sequence:
  MSLRLSSASRRSCPRPTTGSLRLYGGGTSFGTGNSCGISGIGSGFSSAFGGSSSGGNTGG
  GNPCAGFTVNERGLLSGNEKVTMQNLNDRLASYLDSVHALEEANADLEQKIKGWYEKFGP
  GSCRGLDHDYSRYFPIIDDLKNQIIASTTSNANAVLQIDNARLTADDFRLKYENELALHQ
  SVEADVNGLRRVLDEITLCRTDLEIQYETLSEEMTYLKKNHKEEMQVLQCAAGGNVNVEM
  NAAPGVDLTVLLNNMRAEYEALAEQNRRDAEAWFNEKSASLQQQISEDVGATTSARNELT
  EMKRTLQTLEIELQSLLATKHSLECSLTETESNYCAQLAQIQAQIGALEEQLHQVRTETE
  GQKLEYEQLLDIKLHLEKEIETYCLLIGGDDGACKSGGYKSKDYGSGNVGSQVKDPAKAI
  VVKKVLEEVDQRSKILTTRLHSLEEKSQSN
• Function: Essential for the proper assembly of type I and type II keratin protein complexes and formation of keratin intermediate filaments in the inner root sheath (irs). Plays a role in the cytoskeleton organization.
• Tissue Specificity: Strongly expressed in skin and scalp, and weak expression observed in thymus and tongue. In the hair follicle, expressed in Henle layer, Huxley layer and in the inner root sheath cuticle of the hair follicle. Expression extends from the bulb region up to the point of differentiation into the three layers. Also present in the medulla of beard hair (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

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypercholesterolemia, familial, 4	DISFLNLI	Strong	Genetic Variation	[1]
Hypotrichosis 8	DIS2FX7S	Strong	CausalMutation	[2]
Wooly hair, autosomal recessive 3	DISYWD0J	Strong	Autosomal recessive	[3]
Isolated familial wooly hair disorder	DISTWYN7	Supportive	Autosomal dominant	[2]
Hypotrichosis	DISSW933	Limited	Genetic Variation	[4]

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 25 (KRT25).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Keratin, type I cytoskeletal 25 (KRT25).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Keratin, type I cytoskeletal 25 (KRT25).	[6]

References

• [1] Autosomal Recessive Hypotrichosis with Woolly Hair Caused by a Mutation in the Keratin 25 Gene Expressed in Hair Follicles.J Invest Dermatol. 2016 Jun;136(6):1097-1105. doi: 10.1016/j.jid.2016.01.037. Epub 2016 Feb 20.
• [2] A homozygous missense variant in type I keratin KRT25 causes autosomal recessive woolly hair. J Med Genet. 2015 Oct;52(10):676-80. doi: 10.1136/jmedgenet-2015-103255. Epub 2015 Jul 9.
• [3] Mutations in the helix termination motif of mouse type I IRS keratin genes impair the assembly of keratin intermediate filament. Genomics. 2007 Dec;90(6):703-11. doi: 10.1016/j.ygeno.2007.07.013. Epub 2007 Oct 24.
• [4] An epistatic effect of KRT25 on SP6 is involved in curly coat in horses.Sci Rep. 2018 Apr 23;8(1):6374. doi: 10.1038/s41598-018-24865-3.
• [5] 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.
• [6] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [7] 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.