Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPY3BGK)

• DOT Name: SH3 and cysteine-rich domain-containing protein 3 (STAC3)
• Gene Name: STAC3
• Related Disease:
  Bailey-Bloch congenital myopathy
  Congenital myopathy
  Carey-Fineman-Ziter syndrome
  Cerebrovascular disease
  Liver cancer
  Malignant hyperthermia of anesthesia
  Mobius syndrome
  Myopathy
  Ptosis
  Hypokalemic periodic paralysis
  Plasma cell myeloma
• UniProt ID: STAC3_HUMAN
• PDB ID: 2DB6; 6B29; 6UY7; 6UY8; 6UY9
• Pfam ID: PF00130 ; PF00018 ; PF07653 ; PF16664
• Sequence:
  MTEKEVLESPKPSFPAETRQSGLQRLKQLLRKGSTGTKEMELPPEPQANGEAVGAGGGPI
  YYIYEEEEEEEEEEEEPPPEPPKLVNDKPHKFKDHFFKKPKFCDVCARMIVLNNKFGLRC
  KNCKTNIHEHCQSYVEMQRCFGKIPPGFHRAYSSPLYSNQQYACVKDLSAANRNDPVFET
  LRTGVIMANKERKKGQADKKNPVAAMMEEEPESARPEEGKPQDGNPEGDKKAEKKTPDDK
  HKQPGFQQSHYFVALYRFKALEKDDLDFPPGEKITVIDDSNEEWWRGKIGEKVGFFPPNF
  IIRVRAGERVHRVTRSFVGNREIGQITLKKDQIVVQKGDEAGGYVKVYTGRKVGLFPTDF
  LEEI
• Function: Required for normal excitation-contraction coupling in skeletal muscle and for normal muscle contraction in response to membrane depolarization. Required for normal Ca(2+) release from the sarcplasmic reticulum, which ultimately leads to muscle contraction. Probably functions via its effects on muscle calcium channels. Increases CACNA1S channel activity, in addition to its role in enhancing the expression of CACNA1S at the cell membrane. Has a redundant role in promoting the expression of the calcium channel CACNA1S at the cell membrane. Slows down the inactivation rate of the calcium channel CACNA1C.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bailey-Bloch congenital myopathy	DISGFJL6	Definitive	Autosomal recessive	[1]
Congenital myopathy	DISLSK9G	Definitive	Biomarker	[2]
Carey-Fineman-Ziter syndrome	DISURG05	Strong	Genetic Variation	[3]
Cerebrovascular disease	DISAB237	Strong	Biomarker	[4]
Liver cancer	DISDE4BI	Strong	Biomarker	[5]
Malignant hyperthermia of anesthesia	DISYC9XI	Strong	Biomarker	[6]
Mobius syndrome	DIS9YXP5	Strong	Genetic Variation	[3]
Myopathy	DISOWG27	Strong	Genetic Variation	[7]
Ptosis	DISJZNIY	Strong	Genetic Variation	[3]
Hypokalemic periodic paralysis	DISVIXI1	moderate	Altered Expression	[8]
Plasma cell myeloma	DIS0DFZ0	moderate	Altered Expression	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of SH3 and cysteine-rich domain-containing protein 3 (STAC3).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of SH3 and cysteine-rich domain-containing protein 3 (STAC3).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of SH3 and cysteine-rich domain-containing protein 3 (STAC3).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of SH3 and cysteine-rich domain-containing protein 3 (STAC3).	[12]

References

• [1] 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.
• [2] STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility.Hum Mutat. 2018 Dec;39(12):1980-1994. doi: 10.1002/humu.23635. Epub 2018 Oct 11.
• [3] Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome.Am J Med Genet A. 2017 Oct;173(10):2763-2771. doi: 10.1002/ajmg.a.38375. Epub 2017 Aug 4.
• [4] The Efficacy and Safety of 3 Types of Interventions for Stroke Prevention in Patients With Cardiovascular and Cerebrovascular Diseases: A Network Meta-analysis.Clin Ther. 2017 Jul;39(7):1291-1312.e8. doi: 10.1016/j.clinthera.2017.04.008. Epub 2017 Jun 10.
• [5] Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data: The mode of action and predictive models.Toxicol Appl Pharmacol. 2017 Mar 1;318:79-87. doi: 10.1016/j.taap.2017.01.006. Epub 2017 Jan 18.
• [6] Genetic epidemiology of malignant hyperthermia in the UK.Br J Anaesth. 2018 Oct;121(4):944-952. doi: 10.1016/j.bja.2018.06.028. Epub 2018 Aug 17.
• [7] STAC proteins associate to the IQ domain of Ca(V)1.2 and inhibit calcium-dependent inactivation.Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):1376-1381. doi: 10.1073/pnas.1715997115. Epub 2018 Jan 23.
• [8] Stac3 enhances expression of human Ca(V)1.1 in Xenopus oocytes and reveals gating pore currents in HypoPP mutant channels.J Gen Physiol. 2018 Mar 5;150(3):475-489. doi: 10.1085/jgp.201711962. Epub 2018 Jan 31.
• [9] Thiasyrbactins Induce Cell Death via Proteasome Inhibition in Multiple Myeloma Cells.Anticancer Res. 2018 Oct;38(10):5607-5613. doi: 10.21873/anticanres.12895.
• [10] 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.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [13] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.