Details of Drug Off-Target (DOT)

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

• DOT Name: Small muscular protein (SMPX)
• Synonyms: Stretch-responsive skeletal muscle protein
• Gene Name: SMPX
• Related Disease:
  Nonsyndromic genetic hearing loss
  Advanced cancer
  Breast neoplasm
  Classic Hodgkin lymphoma
  Deafness
  Glioblastoma multiforme
  Hearing loss, X-linked 4
  Hereditary angioedema
  leukaemia
  Leukemia
  Myopathy, distal, 7, adult-onset, X-linked
  Neoplasm
  Non-small-cell lung cancer
  Precancerous condition
  Sensorineural hearing loss disorder
  Skin cancer
  Squamous cell carcinoma
  Von willebrand disease
  Breast cancer
  Breast carcinoma
  X-linked nonsyndromic hearing loss
  Kaposi sarcoma
  Cutaneous squamous cell carcinoma
• UniProt ID: SMPX_HUMAN
• Pfam ID: PF15355
• Sequence:
  MNMSKQPVSNVRAIQANINIPMGAFRPGAGQPPRRKECTPEVEEGVPPTSDEEKKPIPGA
  KKLPGPAVNLSEIQNIKSELKYVPKAEQ
• Function: Plays a role in the regulatory network through which muscle cells coordinate their structural and functional states during growth, adaptation, and repair.
• Tissue Specificity: Preferentially and abundantly expressed in heart and skeletal muscle.

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nonsyndromic genetic hearing loss	DISZX61P	Definitive	X-linked	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[4]
Deafness	DISKCLH4	Strong	Genetic Variation	[4]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[5]
Hearing loss, X-linked 4	DISECS9M	Strong	X-linked	[6]
Hereditary angioedema	DIS8X53J	Strong	Genetic Variation	[7]
leukaemia	DISS7D1V	Strong	Altered Expression	[8]
Leukemia	DISNAKFL	Strong	Altered Expression	[8]
Myopathy, distal, 7, adult-onset, X-linked	DISTFPL4	Strong	X-linked	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[11]
Precancerous condition	DISV06FL	Strong	Biomarker	[12]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[13]
Skin cancer	DISTM18U	Strong	Altered Expression	[10]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[14]
Von willebrand disease	DIS3TZCH	Strong	Biomarker	[15]
Breast cancer	DIS7DPX1	moderate	Biomarker	[16]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[16]
X-linked nonsyndromic hearing loss	DISSWCJS	Supportive	X-linked	[17]
Kaposi sarcoma	DISC1H1Z	Disputed	Biomarker	[18]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Biomarker	[2]

10 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 Small muscular protein (SMPX).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Small muscular protein (SMPX).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Small muscular protein (SMPX).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Small muscular protein (SMPX).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Small muscular protein (SMPX).	[23]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Small muscular protein (SMPX).	[20]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Small muscular protein (SMPX).	[24]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Small muscular protein (SMPX).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Small muscular protein (SMPX).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Small muscular protein (SMPX).	[27]

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 Small muscular protein (SMPX).	[28]

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] CSL controls telomere maintenance and genome stability in human dermal fibroblasts.Nat Commun. 2019 Aug 29;10(1):3884. doi: 10.1038/s41467-019-11785-7.
• [3] NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells.Cancer Res. 2008 Mar 15;68(6):1881-8. doi: 10.1158/0008-5472.CAN-07-1597.
• [4] A novel frameshift mutation of SMPX causes a rare form of X-linked nonsyndromic hearing loss in a Chinese family.PLoS One. 2017 May 25;12(5):e0178384. doi: 10.1371/journal.pone.0178384. eCollection 2017.
• [5] Deltex-1 activates mitotic signaling and proliferation and increases the clonogenic and invasive potential of U373 and LN18 glioblastoma cells and correlates with patient survival.PLoS One. 2013;8(2):e57793. doi: 10.1371/journal.pone.0057793. Epub 2013 Feb 25.
• [6] Next-generation sequencing identifies mutations of SMPX, which encodes the small muscle protein, X-linked, as a cause of progressive hearing impairment. Am J Hum Genet. 2011 May 13;88(5):628-34. doi: 10.1016/j.ajhg.2011.04.012. Epub 2011 May 5.
• [7] Population pharmacokinetics of subcutaneous C1-inhibitor for prevention of attacks in patients with hereditary angioedema.Clin Exp Allergy. 2018 Oct;48(10):1325-1332. doi: 10.1111/cea.13220. Epub 2018 Aug 26.
• [8] CSL-MAML-dependent Notch1 signaling controls T lineage-specific IL-7R{alpha} gene expression in early human thymopoiesis and leukemia.J Exp Med. 2009 Apr 13;206(4):779-91. doi: 10.1084/jem.20081922. Epub 2009 Apr 6.
• [9] Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions. Acta Neuropathol. 2021 Aug;142(2):375-393. doi: 10.1007/s00401-021-02319-x. Epub 2021 May 11.
• [10] Autophagy Controls CSL/RBPJ Stability through a p62/SQSTM1-Dependent Mechanism.Cell Rep. 2018 Sep 18;24(12):3108-3114.e4. doi: 10.1016/j.celrep.2018.08.043.
• [11] Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial.Lancet Oncol. 2019 Apr;20(4):494-503. doi: 10.1016/S1470-2045(18)30896-9. Epub 2019 Feb 12.
• [12] Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.Nat Cell Biol. 2015 Sep;17(9):1193-204. doi: 10.1038/ncb3228. Epub 2015 Aug 24.
• [13] A novel mutation in the SMPX gene associated with X-linked nonsyndromic sensorineural hearing loss in a Chinese family.J Hum Genet. 2018 Jun;63(6):723-730. doi: 10.1038/s10038-018-0443-x. Epub 2018 Mar 20.
• [14] Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B.J Clin Invest. 2018 Jun 1;128(6):2581-2599. doi: 10.1172/JCI96915. Epub 2018 May 14.
• [15] Pharmacokinetics, efficacy, and safety of a plasma-derived VWF/FVIII concentrate (VONCENTO) for on-demand and prophylactic treatment in patients with von Willebrand disease (SWIFT-VWD study).Blood Coagul Fibrinolysis. 2017 Mar;28(2):152-162. doi: 10.1097/MBC.0000000000000568.
• [16] Loss of CSL Unlocks a Hypoxic Response and Enhanced Tumor Growth Potential in Breast Cancer Cells.Stem Cell Reports. 2016 May 10;6(5):643-651. doi: 10.1016/j.stemcr.2016.03.004. Epub 2016 Apr 7.
• [17] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [18] A herpesvirus transactivator and cellular POU proteins extensively regulate DNA binding of the host Notch signaling protein RBP-J to the virus genome.J Biol Chem. 2019 Aug 30;294(35):13073-13092. doi: 10.1074/jbc.RA118.007331. Epub 2019 Jul 15.
• [19] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [20] 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.
• [21] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [22] 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.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] 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.
• [25] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [26] 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.
• [27] 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.
• [28] 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.