Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYG2SL7)

• DOT Name: Sarcospan (SSPN)
• Synonyms: K-ras oncogene-associated protein; Kirsten-ras-associated protein
• Gene Name: SSPN
• Related Disease:
  Atrial fibrillation
  Autosomal recessive limb-girdle muscular dystrophy type 2C
  Cardiomyopathy
  Colorectal neoplasm
  Congenital fibrosis of extraocular muscles type 1
  Duchenne muscular dystrophy
  Major depressive disorder
  Mood disorder
  Muscular dystrophy
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4
  Ventricular septal defect
  Cerebrotendinous xanthomatosis
  Endometrial carcinoma
  Familial atrial fibrillation
  Alopecia
  Androgenetic alopecia
  Baldness, male pattern
• UniProt ID: SSPN_HUMAN
• Pfam ID: PF04103
• Sequence:
  MGKNKQPRGQQRQGGPPAADAAGPDDMEPKKGTGAPKECGEEEPRTCCGCRFPLLLALLQ
  LALGIAVTVVGFLMASISSSLLVRDTPFWAGIIVCLVAYLGLFMLCVSYQVDERTCIQFS
  MKLLYFLLSALGLTVCVLAVAFAAHHYSQLTQFTCETTLDSCQCKLPSSEPLSRTFVYRD
  VTDCTSVTGTFKLFLLIQMILNLVCGLVCLLACFVMWKHRYQVFYVGVRICSLTASEGPQ
  QKI
• Function: Component of the dystrophin-glycoprotein complex (DGC), a complex that spans the muscle plasma membrane and forms a link between the F-actin cytoskeleton and the extracellular matrix. Preferentially associates with the sarcoglycan subcomplex of the DGC.
• Tissue Specificity: Isoform 1 is expressed exclusively in heart and skeletal muscle. Isoform 2 is expressed in heart, skeletal muscle, thymus, prostate, testis, ovary, small intestine, colon and spleen.
• 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

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[1]
Autosomal recessive limb-girdle muscular dystrophy type 2C	DISE0ICN	Strong	Biomarker	[2]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[3]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[4]
Congenital fibrosis of extraocular muscles type 1	DISQ4HP6	Strong	Genetic Variation	[5]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Biomarker	[6]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[7]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[7]
Muscular dystrophy	DISJD6P7	Strong	Biomarker	[8]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	DISGM0K5	Strong	Altered Expression	[9]
Ventricular septal defect	DISICO41	Strong	Genetic Variation	[10]
Cerebrotendinous xanthomatosis	DIST9FNK	moderate	Biomarker	[11]
Endometrial carcinoma	DISXR5CY	moderate	Genetic Variation	[12]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[1]
Alopecia	DIS37HU4	Limited	Genetic Variation	[13]
Androgenetic alopecia	DISSJR1P	Limited	Genetic Variation	[14]
Baldness, male pattern	DIS9C9RO	Limited	Genetic Variation	[14]

8 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 Sarcospan (SSPN).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sarcospan (SSPN).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Sarcospan (SSPN).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Sarcospan (SSPN).	[18]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Sarcospan (SSPN).	[19]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Sarcospan (SSPN).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sarcospan (SSPN).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Sarcospan (SSPN).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Sarcospan (SSPN).	[21]

References

• [1] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [2] Molecular and genetic characterization of sarcospan: insights into sarcoglycan-sarcospan interactions.Hum Mol Genet. 2000 Aug 12;9(13):2019-27. doi: 10.1093/hmg/9.13.2019.
• [3] Stabilization of the cardiac sarcolemma by sarcospan rescues DMD-associated cardiomyopathy.JCI Insight. 2019 Apr 30;5(11):e123855. doi: 10.1172/jci.insight.123855.
• [4] Frequent polymorphism of peroxisome proliferator activated receptor gamma gene in colorectal cancer containing wild-type K-ras gene.Int J Mol Med. 2002 May;9(5):485-8.
• [5] Analysis of human sarcospan as a candidate gene for CFEOM1.BMC Genet. 2001;2:3. doi: 10.1186/1471-2156-2-3. Epub 2001 Feb 6.
• [6] Development of a high-throughput screen to identify small molecule enhancers of sarcospan for the treatment of Duchenne muscular dystrophy.Skelet Muscle. 2019 Dec 12;9(1):32. doi: 10.1186/s13395-019-0218-x.
• [7] Analysis of 23andMe antidepressant efficacy survey data: implication of circadian rhythm and neuroplasticity in bupropion response.Transl Psychiatry. 2016 Sep 13;6(9):e889. doi: 10.1038/tp.2016.171.
• [8] Sarcospan integration into laminin-binding adhesion complexes that ameliorate muscular dystrophy requires utrophin and 7 integrin.Hum Mol Genet. 2015 Apr 1;24(7):2011-22. doi: 10.1093/hmg/ddu615. Epub 2014 Dec 11.
• [9] Reduced expression of sarcospan in muscles of Fukuyama congenital muscular dystrophy.Histol Histopathol. 2008 Dec;23(12):1425-38. doi: 10.14670/HH-23.1425.
• [10] Nkx2-5 and Sarcospan genetically interact in the development of the muscular ventricular septum of the heart.Sci Rep. 2017 Apr 13;7:46438. doi: 10.1038/srep46438.
• [11] Sarcospan-dependent Akt activation is required for utrophin expression and muscle regeneration.J Cell Biol. 2012 Jun 25;197(7):1009-27. doi: 10.1083/jcb.201110032.
• [12] Identification of nine new susceptibility loci for endometrial cancer.Nat Commun. 2018 Aug 9;9(1):3166. doi: 10.1038/s41467-018-05427-7.
• [13] Genetic prediction of male pattern baldness.PLoS Genet. 2017 Feb 14;13(2):e1006594. doi: 10.1371/journal.pgen.1006594. eCollection 2017 Feb.
• [14] GWAS for male-pattern baldness identifies 71 susceptibility loci explaining 38% of the risk.Nat Commun. 2017 Nov 17;8(1):1584. doi: 10.1038/s41467-017-01490-8.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] 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.
• [17] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [18] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [19] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [20] 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.
• [21] 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.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [23] 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.