Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2ZSSP4)

• DOT Name: Sodium channel and clathrin linker 1 (SCLT1)
• Synonyms: Sodium channel-associated protein 1
• Gene Name: SCLT1
• Related Disease:
  Alpha thalassemia
  Autosomal recessive polycystic kidney disease
  Beta thalassemia
  Candidiasis
  Chronic obstructive pulmonary disease
  Colitis
  Gastric cancer
  Hepatitis B virus infection
  HIV infectious disease
  Inflammatory bowel disease
  Nephronophthisis
  Oral candidiasis
  Orofaciodigital syndrome I
  Progressive multifocal leukoencephalopathy
  Sjogren-Larsson syndrome
  Stomach cancer
  Vaginal infection
  Ciliopathy
  Metachromatic leukodystrophy
  Vulvovaginal Candidiasis
  Malaria
  Bardet biedl syndrome
  Orofaciodigital syndrome
  Senior-Loken syndrome
• UniProt ID: SCLT1_HUMAN
• Sequence:
  MAAEIDFLREQNRRLNEDFRRYQMESFSKYSSVQKAVCQGEGDDTFENLVFDQSFLAPLV
  TEYDKHLGELNGQLKYYQKQVGEMKLQLENVIKENERLHSELKDAVEKKLEAFPLGTEVG
  TDIYADDETVRNLQEQLQLANQEKTQAVELWQTVSQELDRLHKLYQEHMTEAQIHVFESQ
  KQKDQLFDFQQLTKQLHVTNENMEVTNQQFLKTVTEQSVIIEQLRKKLRQAKLELRVAVA
  KVEELTNVTEDLQGQMKKKEKDVVSAHGREEASDRRLQQLQSSIKQLEIRLCVTIQEANQ
  LRTENTHLEKQTRELQAKCNELENERYEAIVRARNSMQLLEEANLQKSQALLEEKQKEED
  IEKMKETVSRFVQDATIRTKKEVANTKKQCNIQISRLTEELSALQMECAEKQGQIERVIK
  EKKAVEEELEKIYREGRGNESDYRKLEEMHQRFLVSERSKDDLQLRLTRAENRIKQLETD
  SSEEISRYQEMIQKLQNVLESERENCGLVSEQRLKLQQENKQLRKETESLRKIALEAQKK
  AKVKISTMEHEFSIKERGFEVQLREMEDSNRNSIVELRHLLATQQKAANRWKEETKKLTE
  SAEIRINNLKSELSRQKLHTQELLSQLEMANEKVAENEKLILEHQEKANRLQRRLSQAEE
  RAASASQQLSVITVQRRKAASLMNLENI
• Function: Adapter protein that links SCN10A to clathrin. Regulates SCN10A channel activity, possibly by promoting channel internalization.
• Reactome Pathway: Anchoring of the basal body to the plasma membrane (R-HSA-5620912)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alpha thalassemia	DIS5XGK0	Strong	Genetic Variation	[1]
Autosomal recessive polycystic kidney disease	DISPUS40	Strong	Biomarker	[2]
Beta thalassemia	DIS5RCQK	Strong	Genetic Variation	[1]
Candidiasis	DISIRYMU	Strong	Altered Expression	[3]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[4]
Colitis	DISAF7DD	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[6]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[7]
HIV infectious disease	DISO97HC	Strong	Biomarker	[8]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[5]
Nephronophthisis	DISXU4HY	Strong	Biomarker	[9]
Oral candidiasis	DISAVKAH	Strong	Biomarker	[10]
Orofaciodigital syndrome I	DIST27XL	Strong	Genetic Variation	[2]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Biomarker	[11]
Sjogren-Larsson syndrome	DISP943Y	Strong	Genetic Variation	[12]
Stomach cancer	DISKIJSX	Strong	Biomarker	[6]
Vaginal infection	DISVXFB7	Strong	Biomarker	[13]
Ciliopathy	DIS10G4I	moderate	Genetic Variation	[12]
Metachromatic leukodystrophy	DIS3OMWS	moderate	Biomarker	[14]
Vulvovaginal Candidiasis	DISRCR6D	moderate	Biomarker	[15]
Malaria	DISQ9Y50	Disputed	Genetic Variation	[16]
Bardet biedl syndrome	DISTBNZW	Limited	Autosomal recessive	[17]
Orofaciodigital syndrome	DISSB296	Limited	Genetic Variation	[2]
Senior-Loken syndrome	DISGBSGP	Limited	Autosomal recessive	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Sodium channel and clathrin linker 1 (SCLT1).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sodium channel and clathrin linker 1 (SCLT1).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sodium channel and clathrin linker 1 (SCLT1).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sodium channel and clathrin linker 1 (SCLT1).	[22]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Sodium channel and clathrin linker 1 (SCLT1).	[23]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Sodium channel and clathrin linker 1 (SCLT1).	[24]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Sodium channel and clathrin linker 1 (SCLT1).	[25]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Sodium channel and clathrin linker 1 (SCLT1).	[24]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Sodium channel and clathrin linker 1 (SCLT1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sodium channel and clathrin linker 1 (SCLT1).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sodium channel and clathrin linker 1 (SCLT1).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Sodium channel and clathrin linker 1 (SCLT1).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Sodium channel and clathrin linker 1 (SCLT1).	[27]

References

• [1] The clinical significance of the spectrum of interactions of CAP+1 (A-->C), a silent beta-globin gene mutation, with other beta-thalassemia mutations and globin gene modifiers in north Indians.Eur J Haematol. 2007 Nov;79(5):417-21. doi: 10.1111/j.1600-0609.2007.00958.x. Epub 2007 Sep 27.
• [2] Sclt1 deficiency causes cystic kidney by activating ERK and STAT3 signaling.Hum Mol Genet. 2017 Aug 1;26(15):2949-2960. doi: 10.1093/hmg/ddx183.
• [3] Quantitative expression of the Candida albicans secreted aspartyl proteinase gene family in human oral and vaginal candidiasis.Microbiology (Reading). 2008 Nov;154(Pt 11):3266-3280. doi: 10.1099/mic.0.2008/022293-0.
• [4] Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis.Lancet Respir Med. 2014 Mar;2(3):214-25. doi: 10.1016/S2213-2600(14)70002-5. Epub 2014 Feb 7.
• [5] Protein tyrosine phosphatase SAP-1 protects against colitis through regulation of CEACAM20 in the intestinal epithelium.Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):E4264-71. doi: 10.1073/pnas.1510167112. Epub 2015 Jul 20.
• [6] Molecular cloning of a human transmembrane-type protein tyrosine phosphatase and its expression in gastrointestinal cancers.J Biol Chem. 1994 Jan 21;269(3):2075-81.
• [7] Replication of clinical hepatitis B virus isolate and its application for selecting antiviral agents for chronic hepatitis B patients.World J Gastroenterol. 2008 Jun 14;14(22):3490-6. doi: 10.3748/wjg.14.3490.
• [8] Elevated aspartic proteinase secretion and experimental pathogenicity of Candida albicans isolates from oral cavities of subjects infected with human immunodeficiency virus.Infect Immun. 1996 Feb;64(2):466-71. doi: 10.1128/iai.64.2.466-471.1996.
• [9] Mutations of CEP83 cause infantile nephronophthisis and intellectual disability. Am J Hum Genet. 2014 Jun 5;94(6):905-14. doi: 10.1016/j.ajhg.2014.05.002. Epub 2014 May 29.
• [10] In vivo analysis of secreted aspartyl proteinase expression in human oral candidiasis.Infect Immun. 1999 May;67(5):2482-90. doi: 10.1128/IAI.67.5.2482-2490.1999.
• [11] Molecular characterization of a JC virus (Sap-1) clone derived from a cerebellar form of progressive multifocal leukoencephalopathy.Acta Neuropathol. 1992;83(2):105-12. doi: 10.1007/BF00308469.
• [12] Compound heterozygous splice site variants in the SCLT1 gene highlight an additional candidate locus for Senior-Lken syndrome.Sci Rep. 2018 Nov 13;8(1):16733. doi: 10.1038/s41598-018-35152-6.
• [13] The secreted aspartyl proteinases Sap1 and Sap2 cause tissue damage in an in vitro model of vaginal candidiasis based on reconstituted human vaginal epithelium.Infect Immun. 2003 Jun;71(6):3227-34. doi: 10.1128/IAI.71.6.3227-3234.2003.
• [14] The mechanism for a 33-nucleotide insertion in mRNA causing sphingolipid activator protein (SAP-1)-deficient metachromatic leukodystrophy.Hum Genet. 1991 Jun;87(2):211-5. doi: 10.1007/BF00204185.
• [15] Differential expression of Candida albicans secreted aspartyl proteinase in human vulvovaginal candidiasis.Mycoses. 2007 Sep;50(5):383-90. doi: 10.1111/j.1439-0507.2007.01384.x.
• [16] Targeted deletion of SAP1 abolishes the expression of infectivity factors necessary for successful malaria parasite liver infection.Mol Microbiol. 2008 Jul;69(1):152-63. doi: 10.1111/j.1365-2958.2008.06271.x. Epub 2008 May 5.
• [17] Bardet-Biedl syndrome in two unrelated patients with identical compound heterozygous SCLT1 mutations. CEN Case Rep. 2020 Aug;9(3):260-265. doi: 10.1007/s13730-020-00472-y. Epub 2020 Apr 6.
• [18] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [19] 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.
• [20] 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.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [23] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [24] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [25] 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.
• [26] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [27] 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.
• [28] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.