Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD1RD9D)

DOT Name	Homeobox protein SIX6 (SIX6)
Synonyms	Homeodomain protein OPTX2; Optic homeobox 2; Sine oculis homeobox homolog 6
Gene Name	SIX6
Related Disease	Aniridia ( ) Ankylosing spondylitis ( ) Blindness ( ) Breast cancer ( ) Breast carcinoma ( ) Breast neoplasm ( ) Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome ( ) Glaucoma/ocular hypertension ( ) Hepatitis C virus infection ( ) Hypogonadism ( ) Hypogonadotropic hypogonadism 7 with or without anosmia ( ) Kidney failure ( ) Lung adenocarcinoma ( ) Neoplasm ( ) Non-small-cell lung cancer ( ) Open-angle glaucoma ( ) OPTN-related open angle glaucoma ( ) Myopia ( ) Acute lymphocytic leukaemia ( ) Lymphoid leukemia ( ) T-cell acute lymphoblastic leukaemia ( )
UniProt ID	SIX6_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF00046 ; PF16878
Sequence	MFQLPILNFSPQQVAGVCETLEESGDVERLGRFLWSLPVAPAACEALNKNESVLRARAIV AFHGGNYRELYHILENHKFTKESHAKLQALWLEAHYQEAEKLRGRPLGPVDKYRVRKKFP LPRTIWDGEQKTHCFKERTRHLLREWYLQDPYPNPSKKRELAQATGLTPTQVGNWFKNRR QRDRAAAAKNRLQQQVLSQGSGRALRAEGDGTPEVLGVATSPAASLSSKAATSAISITSS DSECDI
Function	May be involved in eye development.
Tissue Specificity	Expressed in the developing and adult retina. Also expressed in the hypothalamic and the pituitary regions.

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Aniridia	DIS1P333	Strong	Genetic Variation	[1]
Ankylosing spondylitis	DISRC6IR	Strong	Biomarker	[2]
Blindness	DISTIM10	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome	DISY2GSJ	Strong	Autosomal recessive	[5]
Glaucoma/ocular hypertension	DISLBXBY	Strong	Genetic Variation	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[7]
Hypogonadism	DISICMNI	Strong	Genetic Variation	[8]
Hypogonadotropic hypogonadism 7 with or without anosmia	DISPBWEU	Strong	Biomarker	[8]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[9]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Altered Expression	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Open-angle glaucoma	DISSZEE8	Strong	Genetic Variation	[12]
OPTN-related open angle glaucoma	DISDR98A	Strong	Genetic Variation	[13]
Myopia	DISK5S60	moderate	Biomarker	[14]
Acute lymphocytic leukaemia	DISPX75S	Limited	Biomarker	[15]
Lymphoid leukemia	DIS65TYQ	Limited	Biomarker	[15]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Limited	Altered Expression	[16]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

6 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 SIX6 (SIX6).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Homeobox protein SIX6 (SIX6).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Homeobox protein SIX6 (SIX6).	[19]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Homeobox protein SIX6 (SIX6).	[20]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Homeobox protein SIX6 (SIX6).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Homeobox protein SIX6 (SIX6).	[20]
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References

1	Mutational screening of 10 genes in Chinese patients with microphthalmia and/or coloboma.Mol Vis. 2009 Dec 27;15:2911-8.
2	UGT2B17 copy number gain in a large ankylosing spondylitis multiplex family.BMC Genet. 2013 Aug 8;14:67. doi: 10.1186/1471-2156-14-67.
3	Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma.PLoS Genet. 2014 May 29;10(5):e1004372. doi: 10.1371/journal.pgen.1004372. eCollection 2014.
4	Expression profile of SIX family members correlates with clinic-pathological features and prognosis of breast cancer: A systematic review and meta-analysis.Medicine (Baltimore). 2016 Jul;95(27):e4085. doi: 10.1097/MD.0000000000004085.
5	Homozygous truncation of SIX6 causes complex microphthalmia in humans. Clin Genet. 2013 Aug;84(2):198-9. doi: 10.1111/cge.12046. Epub 2012 Nov 20.
6	A Common Glaucoma-risk Variant of SIX6 Alters Retinal Nerve Fiber Layer and Optic Disc Measures in a European Population: The EPIC-Norfolk Eye Study.J Glaucoma. 2018 Sep;27(9):743-749. doi: 10.1097/IJG.0000000000001026.
7	Detection of the hepatitis C virus antigen in kidney tissue from infected patients with various glomerulonephritis.Nephrol Dial Transplant. 2009 Sep;24(9):2745-51. doi: 10.1093/ndt/gfp167. Epub 2009 Apr 17.
8	Deletion of the Homeodomain Protein Six6 From GnRH Neurons Decreases GnRH Gene Expression, Resulting in Infertility.Endocrinology. 2019 Sep 1;160(9):2151-2164. doi: 10.1210/en.2019-00113.
9	Exclusion of SIX6 hemizygosity in a child with anophthalmia, panhypopituitarism and renal failure.Am J Med Genet. 2001 Nov 15;104(1):31-6. doi: 10.1002/ajmg.10016.
10	The expression profile and clinic significance of the SIX family in non-small cell lung cancer.J Hematol Oncol. 2016 Nov 8;9(1):119. doi: 10.1186/s13045-016-0339-1.
11	ERBB-2 overexpression as a risk factor for malignant phaeochromocytomas and paraganglinomas.Clin Endocrinol (Oxf). 2016 Jun;84(6):822-9. doi: 10.1111/cen.13019. Epub 2016 Feb 25.
12	Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma.Nat Genet. 2016 Feb;48(2):189-94. doi: 10.1038/ng.3482. Epub 2016 Jan 11.
13	Association of the SIX6 locus with primary open angle glaucoma in southern Chinese and Japanese.Exp Eye Res. 2019 Mar;180:129-136. doi: 10.1016/j.exer.2018.12.014. Epub 2018 Dec 23.
14	Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.Nat Genet. 2013 Mar;45(3):314-8. doi: 10.1038/ng.2554. Epub 2013 Feb 10.
15	Transcriptional activation of prostate specific homeobox gene NKX3-1 in subsets of T-cell lymphoblastic leukemia (T-ALL).PLoS One. 2012;7(7):e40747. doi: 10.1371/journal.pone.0040747. Epub 2012 Jul 27.
16	HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL).Blood. 2005 Jul 1;106(1):274-86. doi: 10.1182/blood-2004-10-3900. Epub 2005 Mar 17.
17	Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
18	Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
19	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.
20	A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
21	Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.