Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWIQDC4)

• DOT Name: Desmoglein-4 (DSG4)
• Synonyms: Cadherin family member 13
• Gene Name: DSG4
• Related Disease:
  Hypotrichosis
  Alopecia
  Aorta coarctation
  Hypercholesterolemia, familial, 4
  Hypotrichosis 6
  Noonan syndrome
  Pemphigus
  Vasculitis due to ADA2 deficiency
  Pemphigus vulgaris
  Hypotrichosis simplex
  Monilethrix
• UniProt ID: DSG4_HUMAN
• Pfam ID: PF01049 ; PF00028
• Sequence:
  MDWLFFRNICLLIILMVVMEVNSEFIVEVKEFDIENGTTKWQTVRRQKREWIKFAAACRE
  GEDNSKRNPIAKIRSDCESNQKITYRISGVGIDRPPYGVFTINPRTGEINITSVVDREIT
  PLFLIYCRALNSRGEDLERPLELRVKVMDINDNAPVFSQSVYTASIEENSDANTLVVKLC
  ATDADEENHLNSKIAYKIVSQEPSGAPMFILNRYTGEVCTMSSFLDREQHSMYNLVVRGS
  DRDGAADGLSSECDCRIKVLDVNDNFPTLEKTSYSASIEENCLSSELIRLQAIDLDEEGT
  DNWLAQYLILSGNDGNWFDIQTDPQTNEGILKVVKMLDYEQAPNIQLSIGVKNQADFHYS
  VASQFQMHPTPVRIQVVDVREGPAFHPSTMAFSVREGIKGSSLLNYVLGTYTAIDLDTGN
  PATDVRYIIGHDAGSWLKIDSRTGEIQFSREFDKKSKYIINGIYTAEILAIDDGSGKTAT
  GTICIEVPDINDYCPNIFPERRTICIDSPSVLISVNEHSYGSPFTFCVVDEPPGIADMWD
  VRSTNATSAILTAKQVLSPGFYEIPILVKDSYNRACELAQMVQLYACDCDDNHMCLDSGA
  AGIYTEDITGDTYGPVTEDQAGVSNVGLGPAGIGMMVLGILLLILAPLLLLLCCCKQRQP
  EGLGTRFAPVPEGGEGVMQSWRIEGAHPEDRDVSNICAPMTASNTQDRMDSSEIYTNTYA
  AGGTVEGGVSGVELNTGMGTAVGLMAAGAAGASGAARKRSSTMGTLRDYADADINMAFLD
  SYFSEKAYAYADEDEGRPANDCLLIYDHEGVGSPVGSIGCCSWIVDDLDESCMETLDPKF
  RTLAEICLNTEIEPFPSHQACIPISTDLPLLGPNYFVNESSGLTPSEVEFQEEMAASEPV
  VHGDIIVTETYGNADPCVQPTTIIFDPQLAPNVVVTEAVMAPVYDIQGNICVPAELADYN
  NVIYAERVLASPGVPDMSNSSTTEGCMGPVMSGNILVGPEIQVMQMMSPDLPIGQTVGST
  SPMTSRHRVTRYSNIHYTQQ
• Function: Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion. Coordinates the transition from proliferation to differentiation in hair follicle keratinocytes.
• Tissue Specificity: Highly expressed in skin, testis and prostate; less in salivary gland. In scalp follicles, present in the inner root sheath (IRS) and all layers of the matrix and precortex.
• Reactome Pathway:
  Formation of the cornified envelope (R-HSA-6809371)
  Keratinization (R-HSA-6805567)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypotrichosis	DISSW933	Definitive	Genetic Variation	[1]
Alopecia	DIS37HU4	Strong	Genetic Variation	[2]
Aorta coarctation	DISAFXDJ	Strong	Biomarker	[3]
Hypercholesterolemia, familial, 4	DISFLNLI	Strong	Biomarker	[4]
Hypotrichosis 6	DIS1A1ZQ	Strong	Autosomal recessive	[5]
Noonan syndrome	DIS7Q7DN	Strong	Biomarker	[6]
Pemphigus	DISZAZ6M	Strong	Biomarker	[7]
Vasculitis due to ADA2 deficiency	DIS1UHPY	Strong	Biomarker	[8]
Pemphigus vulgaris	DISENR62	moderate	Biomarker	[9]
Hypotrichosis simplex	DIS8WHDJ	Supportive	Autosomal dominant	[10]
Monilethrix	DISF9MNT	Supportive	Autosomal dominant	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Desmoglein-4 (DSG4).	[12]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Desmoglein-4 (DSG4).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Desmoglein-4 (DSG4).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Desmoglein-4 (DSG4).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Desmoglein-4 (DSG4).	[16]

References

• [1] A novel deletion mutation in the DSG4 gene underlies autosomal recessive hypotrichosis with variable phenotype in two unrelated consanguineous families.Clin Exp Dermatol. 2015 Jan;40(1):78-84. doi: 10.1111/ced.12457. Epub 2014 Sep 23.
• [2] A novel homozygous variant in the dsp gene underlies the first case of non-syndromic form of alopecia.Arch Dermatol Res. 2015 Nov;307(9):793-801. doi: 10.1007/s00403-015-1590-y. Epub 2015 Jul 7.
• [3] Coarctation of the aorta in Noonan-like syndrome with loose anagen hair.Am J Med Genet A. 2014 May;164A(5):1218-21. doi: 10.1002/ajmg.a.36404. Epub 2014 Jan 23.
• [4] Prevalent LIPH founder mutations lead to loss of P2Y5 activation ability of PA-PLA1alpha in autosomal recessive hypotrichosis.Hum Mutat. 2010 May;31(5):602-10. doi: 10.1002/humu.21235.
• [5] Mutations in the desmoglein 4 gene are associated with monilethrix-like congenital hypotrichosis. J Invest Dermatol. 2006 Jun;126(6):1281-5. doi: 10.1038/sj.jid.5700113.
• [6] Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation.Am J Med Genet A. 2014 Dec;164A(12):3120-5. doi: 10.1002/ajmg.a.36697. Epub 2014 Oct 20.
• [7] Defining the pathogenic involvement of desmoglein 4 in pemphigus and staphylococcal scalded skin syndrome.J Clin Invest. 2004 Nov;114(10):1484-92. doi: 10.1172/JCI20480.
• [8] ADA2 deficiency in a patient with Noonan syndrome-like disorder with loose anagen hair: The co-occurrence of two rare syndromes.Am J Med Genet A. 2019 Dec;179(12):2474-2480. doi: 10.1002/ajmg.a.61363. Epub 2019 Oct 4.
• [9] Desmoglein 4 in hair follicle differentiation and epidermal adhesion: evidence from inherited hypotrichosis and acquired pemphigus vulgaris.Cell. 2003 Apr 18;113(2):249-60. doi: 10.1016/s0092-8674(03)00273-3.
• [10] Recurrent intragenic deletion mutation in desmoglein 4 gene underlies autosomal recessive hypotrichosis in two Pakistani families of Balochi and Sindhi origins. Arch Dermatol Res. 2006 Aug;298(3):135-7. doi: 10.1007/s00403-006-0671-3. Epub 2006 Jun 13.
• [11] An autosomal recessive form of monilethrix is caused by mutations in DSG4: clinical overlap with localized autosomal recessive hypotrichosis. J Invest Dermatol. 2006 Jun;126(6):1292-6. doi: 10.1038/sj.jid.5700251.
• [12] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [15] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [16] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.