Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG1CNND)

• DOT Name: Inward rectifier potassium channel 13 (KCNJ13)
• Synonyms: Inward rectifier K(+) channel Kir7.1; Potassium channel, inwardly rectifying subfamily J member 13
• Gene Name: KCNJ13
• Related Disease:
  Leber congenital amaurosis 1
  Leber congenital amaurosis 16
  Snowflake vitreoretinal degeneration
  Alzheimer disease
  Aural atresia, congenital
  Cataract
  Coronary heart disease
  Inherited retinal dystrophy
  Vitreous syneresis
  Blindness
  Late-onset retinal degeneration
  Vitreoretinal degeneration
  Leber congenital amaurosis
  Retinopathy
  Stroke
• UniProt ID: KCJ13_HUMAN
• Pfam ID: PF01007 ; PF17655
• Sequence:
  MDSSNCKVIAPLLSQRYRRMVTKDGHSTLQMDGAQRGLAYLRDAWGILMDMRWRWMMLVF
  SASFVVHWLVFAVLWYVLAEMNGDLELDHDAPPENHTICVKYITSFTAAFSFSLETQLTI
  GYGTMFPSGDCPSAIALLAIQMLLGLMLEAFITGAFVAKIARPKNRAFSIRFTDTAVVAH
  MDGKPNLIFQVANTRPSPLTSVRVSAVLYQERENGKLYQTSVDFHLDGISSDECPFFIFP
  LTYYHSITPSSPLATLLQHENPSHFELVVFLSAMQEGTGEICQRRTSYLPSEIMLHHCFA
  SLLTRGSKGEYQIKMENFDKTVPEFPTPLVSKSPNRTDLDIHINGQSIDNFQISETGLTE
• Function: Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. KCNJ13 has a very low single channel conductance, low sensitivity to block by external barium and cesium, and no dependence of its inward rectification properties on the internal blocking particle magnesium.
• Tissue Specificity: Predominantly expressed in small intestine. Expression is also detected in stomach, kidney, and all central nervous system regions tested with the exception of spinal cord.
• KEGG Pathway: Protein digestion and absorption (hsa04974)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leber congenital amaurosis 1	DISY2B33	Definitive	Genetic Variation	[1]
Leber congenital amaurosis 16	DIS2HWZU	Definitive	Autosomal recessive	[2]
Snowflake vitreoretinal degeneration	DISXFPWC	Definitive	Autosomal dominant	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Aural atresia, congenital	DISCP7UV	Strong	Biomarker	[5]
Cataract	DISUD7SL	Strong	Genetic Variation	[6]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[7]
Inherited retinal dystrophy	DISGGL77	Strong	Genetic Variation	[6]
Vitreous syneresis	DISYBOSD	Strong	Genetic Variation	[8]
Blindness	DISTIM10	moderate	Genetic Variation	[9]
Late-onset retinal degeneration	DIST9GP4	moderate	Genetic Variation	[10]
Vitreoretinal degeneration	DISVPRKD	moderate	Genetic Variation	[11]
Leber congenital amaurosis	DISMGH8F	Supportive	Autosomal dominant	[12]
Retinopathy	DISB4B0F	Limited	Biomarker	[1]
Stroke	DISX6UHX	Limited	Biomarker	[13]

11 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 Inward rectifier potassium channel 13 (KCNJ13).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Inward rectifier potassium channel 13 (KCNJ13).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Inward rectifier potassium channel 13 (KCNJ13).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inward rectifier potassium channel 13 (KCNJ13).	[17]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Inward rectifier potassium channel 13 (KCNJ13).	[18]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Inward rectifier potassium channel 13 (KCNJ13).	[19]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Inward rectifier potassium channel 13 (KCNJ13).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Inward rectifier potassium channel 13 (KCNJ13).	[20]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Inward rectifier potassium channel 13 (KCNJ13).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Inward rectifier potassium channel 13 (KCNJ13).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Inward rectifier potassium channel 13 (KCNJ13).	[22]

References

• [1] Phagosomal and mitochondrial alterations in RPE may contribute to KCNJ13 retinopathy.Sci Rep. 2019 Mar 7;9(1):3793. doi: 10.1038/s41598-019-40507-8.
• [2] A Novel KCNJ13 Nonsense Mutation and Loss of Kir7.1 Channel Function Causes Leber Congenital Amaurosis (LCA16). Hum Mutat. 2015 Jul;36(7):720-7. doi: 10.1002/humu.22807. Epub 2015 May 20.
• [3] Genetic linkage of snowflake vitreoretinal degeneration to chromosome 2q36. Invest Ophthalmol Vis Sci. 2004 Dec;45(12):4498-503. doi: 10.1167/iovs.04-0722.
• [4] The Brief Memory and Executive Test (BMET): A cognitive screening tool to detect and differentiate vascular cognitive impairment and Alzheimer's disease.Int J Geriatr Psychiatry. 2018 Feb;33(2):e273-e279. doi: 10.1002/gps.4787. Epub 2017 Sep 7.
• [5] Hemorrhage recurrence risk factors in cerebral amyloid angiopathy: Comparative analysis of the overall small vessel disease severity score versus individual neuroimaging markers.J Neurol Sci. 2017 Sep 15;380:64-67. doi: 10.1016/j.jns.2017.07.015. Epub 2017 Jul 9.
• [6] A distinct vitreo-retinal dystrophy with early-onset cataract from recessive KCNJ13 mutations.Ophthalmic Genet. 2015 Mar;36(1):79-84. doi: 10.3109/13816810.2014.985846. Epub 2014 Dec 5.
• [7] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [8] Characterization of the R162W Kir7.1 mutation associated with snowflake vitreoretinopathy.Am J Physiol Cell Physiol. 2013 Mar 1;304(5):C440-9. doi: 10.1152/ajpcell.00363.2012. Epub 2012 Dec 19.
• [9] Gene Augmentation and Readthrough Rescue Channelopathy in an iPSC-RPE Model of Congenital Blindness.Am J Hum Genet. 2019 Feb 7;104(2):310-318. doi: 10.1016/j.ajhg.2018.12.019. Epub 2019 Jan 24.
• [10] Missense variants in the conserved transmembrane M2 protein domain of KCNJ13 associated with retinovascular changes in humans and zebrafish.Exp Eye Res. 2019 Dec;189:107852. doi: 10.1016/j.exer.2019.107852. Epub 2019 Oct 21.
• [11] Mutations in KCNJ13 cause autosomal-dominant snowflake vitreoretinal degeneration. Am J Hum Genet. 2008 Jan;82(1):174-80. doi: 10.1016/j.ajhg.2007.08.002.
• [12] Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis. Am J Hum Genet. 2011 Jul 15;89(1):183-90. doi: 10.1016/j.ajhg.2011.06.002.
• [13] Perivascular spaces contribute to cognition beyond other small vessel disease markers.Neurology. 2019 Mar 19;92(12):e1309-e1321. doi: 10.1212/WNL.0000000000007124. Epub 2019 Feb 27.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] 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.
• [16] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [17] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [18] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [19] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [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] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.