Details of Drug Off-Target (DOT)

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

• DOT Name: Filaggrin-2 (FLG2)
• Synonyms: FLG-2; Intermediate filament-associated and psoriasis-susceptibility protein; Ifapsoriasin
• Gene Name: FLG2
• Related Disease:
  Atopic dermatitis
  Peeling skin syndrome 1
  Peeling skin syndrome 6
  Pseudomonas infection
  Peeling skin syndrome type A
  Granular corneal dystrophy type II
• UniProt ID: FILA2_HUMAN
• Pfam ID: PF01023
• Sequence:
  MTDLLRSVVTVIDVFYKYTKQDGECGTLSKGELKELLEKELHPVLKNPDDPDTVDVIMHM
  LDRDHDRRLDFTEFLLMIFKLTMACNKVLSKEYCKASGSKKHRRGHRHQEEESETEEDEE
  DTPGHKSGYRHSSWSEGEEHGYSSGHSRGTVKCRHGSNSRRLGRQGNLSSSGNQEGSQKR
  YHRSSCGHSWSGGKDRHGSSSVELRERINKSHISPSRESGEEYESGSGSNSWERKGHGGL
  SCGLETSGHESNSTQSRIREQKLGSSCSGSGDSGRRSHACGYSNSSGCGRPQNASSSCQS
  HRFGGQGNQFSYIQSGCQSGIKGGQGHGCVSGGQPSGCGQPESNPCSQSYSQRGYGAREN
  GQPQNCGGQWRTGSSQSSCCGQYGSGGSQSCSNGQHEYGSCGRFSNSSSSNEFSKCDQYG
  SGSSQSTSFEQHGTGLSQSSGFEQHVCGSGQTCGQHESTSSQSLGYDQHGSSSGKTSGFG
  QHGSGSGQSSGFGQCGSGSGQSSGFGQHGSVSGQSSGFGQHGSVSGQSSGFGQHESRSRQ
  SSYGQHGSGSSQSSGYGQYGSRETSGFGQHGLGSGQSTGFGQYGSGSGQSSGFGQHGSGS
  GQSSGFGQHESRSGQSSYGQHSSGSSQSSGYGQHGSRQTSGFGQHGSGSSQSTGFGQYGS
  GSGQSSGFGQHVSGSGQSSGFGQHESRSGHSSYGQHGFGSSQSSGYGQHGSSSGQTSGFG
  QHELSSGQSSSFGQHGSGSGQSSGFGQHGSGSGQSSGFGQHESRSGQSSYGQHSSGSSQS
  SGYGQHGSRQTSGFGQHGSGSSQSTGFGQYGSGSGQSAGFGQHGSGSGQSSGFGQHESRS
  HQSSYGQHGSGSSQSSGYGQHGSSSGQTSGFGQHRSSSGQYSGFGQHGSGSGQSSGFGQH
  GTGSGQYSGFGQHESRSHQSSYGQHGSGSSQSSGYGQHGSSSGQTFGFGQHRSGSGQSSG
  FGQHGSGSGQSSGFGQHESGSGKSSGFGQHESRSSQSNYGQHGSGSSQSSGYGQHGSSSG
  QTTGFGQHRSSSGQYSGFGQHGSGSDQSSGFGQHGTGSGQSSGFGQYESRSRQSSYGQHG
  SGSSQSSGYGQHGSNSGQTSGFGQHRPGSGQSSGFGQYGSGSGQSSGFGQHGSGTGKSSG
  FAQHEYRSGQSSYGQHGTGSSQSSGCGQHESGSGPTTSFGQHVSGSDNFSSSGQHISDSG
  QSTGFGQYGSGSGQSTGLGQGESQQVESGSTVHGRQETTHGQTINTTRHSQSGQGQSTQT
  GSRVTRRRRSSQSENSDSEVHSKVSHRHSEHIHTQAGSHYPKSGSTVRRRQGTTHGQRGD
  TTRHGHSGHGQSTQTGSRTSGRQRFSHSDATDSEVHSGVSHRPHSQEQTHSQAGSQHGES
  ESTVHERHETTYGQTGEATGHGHSGHGQSTQRGSRTTGRRGSGHSESSDSEVHSGGSHRP
  QSQEQTHGQAGSQHGESGSTVHGRHGTTHGQTGDTTRHAHYHHGKSTQRGSSTTGRRGSG
  HSESSDSEVHSGGSHTHSGHTHGQSGSQHGESESIIHDRHRITHGQTGDTTRHSYSGHEQ
  TTQTGSRTTGRQRTSHSESTDSEVHSGGSHRPHSREHTYGQAGSQHEEPEFTVHERHGTT
  HGQIGDTTGHSHSGHGQSTQRGSRTTGRQRSSHSESSDSEVHSGVSHTHTGHTHGQAGSQ
  HGQSESIVPERHGTTHGQTGDTTRHAHYHHGLTTQTGSRTTGRRGSGHSEYSDSEGYSGV
  SHTHSGHTHGQARSQHGESESIVHERHGTIHGQTGDTTRHAHSGHGQSTQTGSRTTGRRS
  SGHSEYSDSEGHSGFSQRPHSRGHTHGQAGSQHGESESIVDERHGTTHGQTGDTSGHSQS
  GHGQSTQSGSSTTGRRRSGHSESSDSEVHSGGSHTHSGHTHSQARSQHGESESTVHKRHQ
  TTHGQTGDTTEHGHPSHGQTIQTGSRTTGRRGSGHSEYSDSEGPSGVSHTHSGHTHGQAG
  SHYPESGSSVHERHGTTHGQTADTTRHGHSGHGQSTQRGSRTTGRRASGHSEYSDSEGHS
  GVSHTHSGHAHGQAGSQHGESGSSVHERHGTTHGQTGDTTRHAHSGHGQSTQRGSRTAGR
  RGSGHSESSDSEVHSGVSHTHSGHTYGQARSQHGESGSAIHGRQGTIHGQTGDTTRHGQS
  GHGQSTQTGSRTTGRQRSSHSESSDSEVHSEASPTHSGHTHSQAGSRHGQSGSSGHGRQG
  TTHGQTGDTTRHAHYGYGQSTQRGSRTTGRRGSGHSESSDSEVHSWGSHTHSGHIQGQAG
  SQQRQPGSTVHGRLETTHGQTGDTTRHGHSGYGQSTQTGSRSSRASHFQSHSSERQRHGS
  SQVWKHGSYGPAEYDYGHTGYGPSGGSRKSISNSHLSWSTDSTANKQLSRH
• Function: Essential for normal cell-cell adhesion in the cornified cell layers. Important for proper integrity and mechanical strength of the stratum corneum of the epidermis.
• Tissue Specificity: Expressed in skin, thymus, stomach and placenta, but not detected in heart, brain, liver, lung, bone marrow, small intestine, spleen, prostate, colon, adrenal gland, kidney, pancreas, mammary gland, bladder, thyroid, salivary gland and trachea. Weakly expressed in esophagus, tonsils and testis (at protein level). In the skin, strongly expressed in the upper stratum granulosum and lower stratum corneum, but not detected in the upper stratum corneum (at protein level) . In scalp hair follicles, mainly restricted within the granular and cornified cells surrounding the infundibular outer root sheath, with weak expression in central and proximal outer root sheath (at protein level). Tends to be down-regulated in sporiatic lesions compared to non-lesional skin inthe same patients .
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atopic dermatitis	DISTCP41	Strong	Altered Expression	[1]
Peeling skin syndrome 1	DIS35574	Strong	Biomarker	[2]
Peeling skin syndrome 6	DIS1A5FE	Strong	Autosomal recessive	[3]
Pseudomonas infection	DIS9WYLA	Strong	Biomarker	[4]
Peeling skin syndrome type A	DIS05EXP	Supportive	Autosomal recessive	[5]
Granular corneal dystrophy type II	DISAEE20	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Filaggrin-2 (FLG2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Filaggrin-2 (FLG2).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Filaggrin-2 (FLG2).	[8]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Filaggrin-2 (FLG2).	[8]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Filaggrin-2 (FLG2).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Filaggrin-2 (FLG2).	[10]

References

• [1] Expression of Cornified Envelope Proteins in Skin and Its Relationship with Atopic Dermatitis Phenotype.Acta Derm Venereol. 2017 Jan 4;97(1):36-41. doi: 10.2340/00015555-2482.
• [2] Filaggrin 2 Deficiency Results in Abnormal Cell-Cell Adhesion in the Cornified Cell Layers and Causes Peeling Skin Syndrome Type A. J Invest Dermatol. 2018 Aug;138(8):1736-1743. doi: 10.1016/j.jid.2018.04.032. Epub 2018 Jun 27.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] Skin-Derived C-Terminal Filaggrin-2 Fragments Are Pseudomonas aeruginosa-Directed Antimicrobials Targeting Bacterial Replication.PLoS Pathog. 2015 Sep 15;11(9):e1005159. doi: 10.1371/journal.ppat.1005159. eCollection 2015 Sep.
• [5] Peeling skin syndrome associated with novel variant in FLG2 gene. Am J Med Genet A. 2017 Dec;173(12):3201-3204. doi: 10.1002/ajmg.a.38468. Epub 2017 Sep 8.
• [6] Skin barrier damage after exposure to paraphenylenediamine.J Allergy Clin Immunol. 2020 Feb;145(2):619-631.e2. doi: 10.1016/j.jaci.2019.11.023. Epub 2019 Nov 26.
• [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] Retinoic acid and hydroquinone induce inverse expression patterns on cornified envelope-associated proteins: implication in skin irritation. J Dermatol Sci. 2014 Nov;76(2):112-9. doi: 10.1016/j.jdermsci.2014.08.003. Epub 2014 Aug 26.
• [9] 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.
• [10] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.