Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT1I9WY)

• DOT Name: Homeobox protein SIX5 (SIX5)
• Synonyms: DM locus-associated homeodomain protein; Sine oculis homeobox homolog 5
• Gene Name: SIX5
• Related Disease:
  Branchiootorenal syndrome 2
  Coronary heart disease
  Myotonic dystrophy type 1
  Autoimmune disease
  Bronchiolitis obliterans syndrome
  Cataract
  Branchio-oto-renal syndrome
  Myotonic dystrophy
• UniProt ID: SIX5_HUMAN
• Pfam ID: PF00046 ; PF16878
• Sequence:
  MATLPAEPSAGPAAGGEAVAAAAATEEEEEEARQLLQTLQAAEGEAAAAAGAGAGAAAAG
  AEGPGSPGVPGSPPEAASEPPTGLRFSPEQVACVCEALLQAGHAGRLSRFLGALPPAERL
  RGSDPVLRARALVAFQRGEYAELYRLLESRPFPAAHHAFLQDLYLRARYHEAERARGRAL
  GAVDKYRLRKKFPLPKTIWDGEETVYCFKERSRAALKACYRGNRYPTPDEKRRLATLTGL
  SLTQVSNWFKNRRQRDRTGAGGGAPCKSESDGNPTTEDESSRSPEDLERGAAPVSAEAAA
  QGSIFLAGTGPPAPCPASSSILVNGSFLAASGSPAVLLNGGPVIINGLALGEASSLGPLL
  LTGGGGAPPPQPSPQGASETKTSLVLDPQTGEVRLEEAQSEAPETKGAQVAAPGPALGEE
  VLGPLAQVVPGPPTAATFPLPPGPVPAVAAPQVVPLSPPPGYPTGLSPTSPLLNLPQVVP
  TSQVVTLPQAVGPLQLLAAGPGSPVKVAAAAGPANVHLINSGVGVTALQLPSATAPGNFL
  LANPVSGSPIVTGVALQQGKIILTATFPTSMLVSQVLPPAPGLALPLKPETAISVPEGGL
  PVAPSPALPEAHALGTLSAQQPPPAAATTSSTSLPFSPDSPGLLPNFPAPPPEGLMLSPA
  AVPVWSAGLELSAGTEGLLEAEKGLGTQAPHTVLRLPDPDPEGLLLGATAGGEVDEGLEA
  EAKVLTQLQSVPVEEPLEL
• Function: Transcription factor that is thought to be involved in regulation of organogenesis. May be involved in determination and maintenance of retina formation. Binds a 5'-GGTGTCAG-3' motif present in the ARE regulatory element of ATP1A1. Binds a 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 element in the myogenin promoter, and in the IGFBP5 promoter. Thought to be regulated by association with Dach and Eya proteins, and seems to be coactivated by EYA1, EYA2 and EYA3.
• Tissue Specificity: Expressed in adult but not in fetal eyes. Found in corneal epithelium and endothelium, lens epithelium, ciliary body epithelia, cellular layers of the retina and the sclera.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Branchiootorenal syndrome 2	DISEB137	Definitive	Autosomal dominant	[1]
Coronary heart disease	DIS5OIP1	Definitive	Genetic Variation	[2]
Myotonic dystrophy type 1	DISJC0OX	Definitive	Altered Expression	[3]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[4]
Bronchiolitis obliterans syndrome	DISCK9IV	Strong	Biomarker	[5]
Cataract	DISUD7SL	Strong	Altered Expression	[6]
Branchio-oto-renal syndrome	DISIPQ53	Supportive	Autosomal dominant	[7]
Myotonic dystrophy	DISNBEMX	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Homeobox protein SIX5 (SIX5).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Homeobox protein SIX5 (SIX5).	[10]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Homeobox protein SIX5 (SIX5).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Homeobox protein SIX5 (SIX5).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Homeobox protein SIX5 (SIX5).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Homeobox protein SIX5 (SIX5).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Homeobox protein SIX5 (SIX5).	[15]

References

• [1] Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome. Am J Hum Genet. 2007 Apr;80(4):800-4. doi: 10.1086/513322. Epub 2007 Feb 22.
• [2] Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults.Int J Epidemiol. 2017 Aug 1;46(4):1211-1222. doi: 10.1093/ije/dyw245.
• [3] Identification of transcriptional targets for Six5: implication for the pathogenesis of myotonic dystrophy type 1.Hum Mol Genet. 2002 May 1;11(9):1045-58. doi: 10.1093/hmg/11.9.1045.
• [4] Defining the genetic origins of three rheumatoid synovium-derived IgG rheumatoid factors.J Clin Invest. 1994 Jun;93(6):2545-53. doi: 10.1172/JCI117265.
• [5] Whole exome sequencing identifies a mutation in EYA1 and GLI3 in a patient with branchiootic syndrome and esophageal atresia: Coincidence or a digenic mode of inheritance?.Mol Med Rep. 2018 Feb;17(2):3200-3205. doi: 10.3892/mmr.2017.8196. Epub 2017 Dec 6.
• [6] Characterization of the expression of DMPK and SIX5 in the human eye and implications for pathogenesis in myotonic dystrophy.Hum Mol Genet. 1999 Mar;8(3):481-92. doi: 10.1093/hmg/8.3.481.
• [7] Branchiootorenal Spectrum Disorder. 1999 Mar 19 [updated 2018 Sep 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [8] Transgenic mouse models for myotonic dystrophy type 1 (DM1).Cytogenet Genome Res. 2003;100(1-4):230-42. doi: 10.1159/000072859.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [12] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [15] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.