Details of Drug Off-Target (DOT)

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

• DOT Name: Amiloride-sensitive sodium channel subunit gamma (SCNN1G)
• Synonyms: Epithelial Na(+) channel subunit gamma; ENaCG; Gamma-ENaC; Gamma-NaCH; Nonvoltage-gated sodium channel 1 subunit gamma; SCNEG
• Gene Name: SCNN1G
• Related Disease:
  Liddle syndrome
  Autosomal dominant pseudohypoaldosteronism type 1
  Autosomal recessive pseudohypoaldosteronism type 1
  Bronchiectasis
  Bronchiectasis with or without elevated sweat chloride 3
  Cystic fibrosis
  Hypercalcaemia
  Hypotension
  Idiopathic bronchiectasis
  Liddle syndrome 2
  Pancreatic cancer
  Pelger-Huet anomaly
  Pseudohypoaldosteronism type 2
  Pyelonephritis
  Squamous cell carcinoma
  Ulcerative colitis
  Urinary tract infection
  Nephropathy
  High blood pressure
  Pulmonary disease
• UniProt ID: SCNNG_HUMAN
• PDB ID: 6BQN; 6WTH
• Pfam ID: PF00858
• Sequence:
  MAPGEKIKAKIKKNLPVTGPQAPTIKELMRWYCLNTNTHGCRRIVVSRGRLRRLLWIGFT
  LTAVALILWQCALLVFSFYTVSVSIKVHFRKLDFPAVTICNINPYKYSTVRHLLADLEQE
  TREALKSLYGFPESRKRREAESWNSVSEGKQPRFSHRIPLLIFDQDEKGKARDFFTGRKR
  KVGGSIIHKASNVMHIESKQVVGFQLCSNDTSDCATYTFSSGINAIQEWYKLHYMNIMAQ
  VPLEKKINMSYSAEELLVTCFFDGVSCDARNFTLFHHPMHGNCYTFNNRENETILSTSMG
  GSEYGLQVILYINEEEYNPFLVSSTGAKVIIHRQDEYPFVEDVGTEIETAMVTSIGMHLT
  ESFKLSEPYSQCTEDGSDVPIRNIYNAAYSLQICLHSCFQTKMVEKCGCAQYSQPLPPAA
  NYCNYQQHPNWMYCYYQLHRAFVQEELGCQSVCKEACSFKEWTLTTSLAQWPSVVSEKWL
  LPVLTWDQGRQVNKKLNKTDLAKLLIFYKDLNQRSIMESPANSIEMLLSNFGGQLGLWMS
  CSVVCVIEIIEVFFIDFFSIIARRQWQKAKEWWAWKQAPPCPEAPRSPQGQDNPALDIDD
  DLPTFNSALHLPPALGTQVPGTPPPKYNTLRLERAFSNQLTDTQMLDEL
• Function: Sodium permeable non-voltage-sensitive ion channel inhibited by the diuretic amiloride. Mediates the electrodiffusion of the luminal sodium (and water, which follows osmotically) through the apical membrane of epithelial cells. Plays an essential role in electrolyte and blood pressure homeostasis, but also in airway surface liquid homeostasis, which is important for proper clearance of mucus. Controls the reabsorption of sodium in kidney, colon, lung and sweat glands. Also plays a role in taste perception.
• Tissue Specificity: Expressed in kidney (at protein level).
• KEGG Pathway:
  Taste transduction (hsa04742)
  Aldosterone-regulated sodium reabsorption (hsa04960)
• Reactome Pathway:
  Sensory perception of salty taste (R-HSA-9730628)
  Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Liddle syndrome	DISY0X0N	Definitive	Autosomal dominant	[1]
Autosomal dominant pseudohypoaldosteronism type 1	DIS4FXQ4	Strong	Biomarker	[2]
Autosomal recessive pseudohypoaldosteronism type 1	DIS7WSWQ	Strong	Autosomal recessive	[3]
Bronchiectasis	DIS5MYEE	Strong	Genetic Variation	[4]
Bronchiectasis with or without elevated sweat chloride 3	DISFZU2Y	Strong	Autosomal dominant	[5]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[6]
Hypercalcaemia	DISKQ2K7	Strong	Biomarker	[7]
Hypotension	DISYNSM9	Strong	Biomarker	[8]
Idiopathic bronchiectasis	DISZ7YNI	Strong	GermlineCausalMutation	[9]
Liddle syndrome 2	DIS0BZCF	Strong	Autosomal dominant	[10]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[7]
Pelger-Huet anomaly	DISCW4OI	Strong	Biomarker	[11]
Pseudohypoaldosteronism type 2	DISFTCHO	Strong	Biomarker	[2]
Pyelonephritis	DISAOX93	Strong	Biomarker	[12]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[7]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[13]
Urinary tract infection	DISMT6UV	Strong	Biomarker	[12]
Nephropathy	DISXWP4P	moderate	Genetic Variation	[14]
High blood pressure	DISY2OHH	Disputed	Biomarker	[15]
Pulmonary disease	DIS6060I	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Amiloride-sensitive sodium channel subunit gamma (SCNN1G).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Amiloride-sensitive sodium channel subunit gamma (SCNN1G).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Amiloride-sensitive sodium channel subunit gamma (SCNN1G).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Amiloride-sensitive sodium channel subunit gamma (SCNN1G).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Amiloride-sensitive sodium channel subunit gamma (SCNN1G).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Amiloride-sensitive sodium channel subunit gamma (SCNN1G).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Amiloride-sensitive sodium channel subunit gamma (SCNN1G).	[20]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Amiloride-sensitive sodium channel subunit gamma (SCNN1G).	[21]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Amiloride-sensitive sodium channel subunit gamma (SCNN1G).	[23]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Amiloride-sensitive sodium channel subunit gamma (SCNN1G).	[24]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Amiloride-sensitive sodium channel subunit gamma (SCNN1G).	[25]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone increases the expression of Amiloride-sensitive sodium channel subunit gamma (SCNN1G).	[26]
Aldosterone	DM9S2JW	Approved	Aldosterone increases the expression of Amiloride-sensitive sodium channel subunit gamma (SCNN1G).	[27]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Amiloride-sensitive sodium channel subunit gamma (SCNN1G).	[24]
MG-101	DM3RUT8	Investigative	MG-101 decreases the expression of Amiloride-sensitive sodium channel subunit gamma (SCNN1G).	[19]

References

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• [2] A novel splice-site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families.Nat Genet. 1996 Jun;13(2):248-50. doi: 10.1038/ng0696-248.
• [3] Compound heterozygous mutations in the gamma subunit gene of ENaC (1627delG and 1570-1G-->A) in one sporadic Japanese patient with a systemic form of pseudohypoaldosteronism type 1. J Clin Endocrinol Metab. 2001 Jan;86(1):9-12. doi: 10.1210/jcem.86.1.7116.
• [4] Could a defective epithelial sodium channel lead to bronchiectasis.Respir Res. 2008 May 28;9(1):46. doi: 10.1186/1465-9921-9-46.
• [5] PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels. Nat Genet. 2019 Nov;51(11):1560-1565. doi: 10.1038/s41588-019-0528-2.
• [6] Antisense oligonucleotide targeting of mRNAs encoding ENaC subunits , , and improves cystic fibrosis-like disease in mice.J Cyst Fibros. 2019 May;18(3):334-341. doi: 10.1016/j.jcf.2018.07.006. Epub 2018 Aug 10.
• [7] Effect of combination treatment with a vitamin D analog (OCT) and a bisphosphonate (AHPrBP) in a nude mouse model of cancer-associated hypercalcemia.J Bone Miner Res. 1998 Sep;13(9):1378-83. doi: 10.1359/jbmr.1998.13.9.1378.
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• [13] Cytokine-dependent transcriptional down-regulation of epithelial sodium channel in ulcerative colitis.Gastroenterology. 2004 Jun;126(7):1711-20. doi: 10.1053/j.gastro.2004.03.010.
• [14] A novel SCNN1G mutation in a PHA I infant patient correlates with nephropathy.Biochem Biophys Res Commun. 2019 Nov 5;519(2):415-421. doi: 10.1016/j.bbrc.2019.07.026. Epub 2019 Sep 12.
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• [16] The TNFalpha receptor TNFRSF1A and genes encoding the amiloride-sensitive sodium channel ENaC as modulators in cystic fibrosis.Hum Genet. 2006 Apr;119(3):331-43. doi: 10.1007/s00439-006-0140-2. Epub 2006 Feb 4.
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• [26] P2Y receptor regulation of sodium transport in human mammary epithelial cells. Am J Physiol Cell Physiol. 2007 Nov;293(5):C1472-80. doi: 10.1152/ajpcell.00068.2007. Epub 2007 Aug 22.
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• [29] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.