Details of Drug Off-Target (DOT)

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

• DOT Name: Alpha-1-syntrophin (SNTA1)
• Synonyms: 59 kDa dystrophin-associated protein A1 acidic component 1; Pro-TGF-alpha cytoplasmic domain-interacting protein 1; TACIP1; Syntrophin-1
• Gene Name: SNTA1
• Related Disease:
  Atrial fibrillation
  Breast cancer
  Breast carcinoma
  Dementia
  Duchenne muscular dystrophy
  Hypertrophic cardiomyopathy
  Metastatic malignant neoplasm
  Short QT syndrome
  Narcolepsy type 1
  Long QT syndrome
  Status epilepticus seizure
  Advanced cancer
  Arrhythmia
  Long QT syndrome 12
• UniProt ID: SNTA1_HUMAN
• Pfam ID: PF00595 ; PF00169 ; PF18012
• Sequence:
  MASGRRAPRTGLLELRAGAGSGAGGERWQRVLLSLAEDVLTVSPADGDPGPEPGAPREQE
  PAQLNGAAEPGAGPPQLPEALLLQRRRVTVRKADAGGLGISIKGGRENKMPILISKIFKG
  LAADQTEALFVGDAILSVNGEDLSSATHDEAVQVLKKTGKEVVLEVKYMKDVSPYFKNST
  GGTSVGWDSPPASPLQRQPSSPGPTPRNFSEAKHMSLKMAYVSKRCTPNDPEPRYLEICS
  ADGQDTLFLRAKDEASARSWATAIQAQVNTLTPRVKDELQALLAATSTAGSQDIKQIGWL
  TEQLPSGGTAPTLALLTEKELLLYLSLPETREALSRPARTAPLIATRLVHSGPSKGSVPY
  DAELSFALRTGTRHGVDTHLFSVESPQELAAWTRQLVDGCHRAAEGVQEVSTACTWNGRP
  CSLSVHIDKGFTLWAAEPGAARAVLLRQPFEKLQMSSDDGASLLFLDFGGAEGEIQLDLH
  SCPKTIVFIIHSFLSAKVTRLGLLA
• Function: Adapter protein that binds to and probably organizes the subcellular localization of a variety of membrane proteins. May link various receptors to the actin cytoskeleton and the extracellular matrix via the dystrophin glycoprotein complex. Plays an important role in synapse formation and in the organization of UTRN and acetylcholine receptors at the neuromuscular synapse. Binds to phosphatidylinositol 4,5-bisphosphate.
• Tissue Specificity: High expression in skeletal muscle and heart. Low expression in brain, pancreas, liver, kidney and lung. Not detected in placenta.
• KEGG Pathway:
  Cytoskeleton in muscle cells (hsa04820)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
  Viral myocarditis (hsa05416)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Dementia	DISXL1WY	Strong	Genetic Variation	[3]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Biomarker	[4]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Biomarker	[5]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[6]
Short QT syndrome	DISOI9X1	Strong	Genetic Variation	[7]
Narcolepsy type 1	DISH7Y6Q	moderate	Altered Expression	[8]
Long QT syndrome	DISMKWS3	Disputed	Autosomal dominant	[9]
Status epilepticus seizure	DISY3BIC	Disputed	Biomarker	[10]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[2]
Arrhythmia	DISFF2NI	Limited	Genetic Variation	[11]
Long QT syndrome 12	DISP9J6O	Limited	Autosomal dominant	[12]

3 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 Alpha-1-syntrophin (SNTA1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Alpha-1-syntrophin (SNTA1).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Alpha-1-syntrophin (SNTA1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Alpha-1-syntrophin (SNTA1).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Alpha-1-syntrophin (SNTA1).	[15]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Alpha-1-syntrophin (SNTA1).	[16]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Alpha-1-syntrophin (SNTA1).	[17]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Alpha-1-syntrophin (SNTA1).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Alpha-1-syntrophin (SNTA1).	[19]

References

• [1] Functional consequences of genetic variation in sodium channel modifiers in early onset lone atrial fibrillation.Per Med. 2018 Mar;15(2):93-102. doi: 10.2217/pme-2017-0076. Epub 2018 Jan 31.
• [2] Role of SNTA1 in Rac1 activation, modulation of ROS generation, and migratory potential of human breast cancer cells.Br J Cancer. 2014 Feb 4;110(3):706-14. doi: 10.1038/bjc.2013.723. Epub 2014 Jan 16.
• [3] Transcriptional network analysis of human astrocytic endfoot genes reveals region-specific associations with dementia status and tau pathology.Sci Rep. 2018 Aug 17;8(1):12389. doi: 10.1038/s41598-018-30779-x.
• [4] Involvement of TRPV2 and SOCE in calcium influx disorder in DMD primary human myotubes with a specific contribution of 1-syntrophin and PLC/PKC in SOCE regulation.Am J Physiol Cell Physiol. 2013 May 1;304(9):C881-94. doi: 10.1152/ajpcell.00182.2012. Epub 2013 Feb 20.
• [5] Genetics of sudden cardiac death syndromes.Curr Opin Cardiol. 2011 May;26(3):196-203. doi: 10.1097/HCO.0b013e3283459893.
• [6] Potential markers of tongue tumor progression selected by cDNA microarray.Int J Immunopathol Pharmacol. 2005 Jul-Sep;18(3):513-24. doi: 10.1177/039463200501800311.
• [7] Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths.Circ Genom Precis Med. 2018 Jan;11(1):e001817. doi: 10.1161/CIRCGEN.117.001817. Epub 2018 Jan 11.
• [8] Prostaglandin D2 Receptor DP1 Antibodies Predict Vaccine-induced and Spontaneous Narcolepsy Type 1: Large-scale Study of Antibody Profiling.EBioMedicine. 2018 Mar;29:47-59. doi: 10.1016/j.ebiom.2018.01.043. Epub 2018 Feb 2.
• [9] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [10] Astroglial loss and edema formation in the rat piriform cortex and hippocampus following pilocarpine-induced status epilepticus.J Comp Neurol. 2010 Nov 15;518(22):4612-28. doi: 10.1002/cne.22482.
• [11] Digenic inheritance novel mutations in SCN5a and SNTA1 increase late I(Na) contributing to LQT syndrome.Am J Physiol Heart Circ Physiol. 2013 Apr 1;304(7):H994-H1001. doi: 10.1152/ajpheart.00705.2012. Epub 2013 Feb 1.
• [12] 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.
• [13] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [14] 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.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [18] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [19] 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.
• [20] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [21] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.