Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSJ3QGX)

• DOT Name: Leiomodin-3 (LMOD3)
• Synonyms: Leiomodin, fetal form
• Gene Name: LMOD3
• Related Disease:
  Congenital myopathy
  Nemaline myopathy 10
  Nemaline myopathy
  Severe congenital nemaline myopathy
  Typical nemaline myopathy
• UniProt ID: LMOD3_HUMAN
• Pfam ID: PF03250
• Sequence:
  MSEHSRNSDQEELLDEEINEDEILANLSAEELKELQSEMEVMAPDPSLPVGMIQKDQTDK
  PPTGNFNHKSLVDYMYWEKASRRMLEEERVPVTFVKSEEKTQEEHEEIEKRNKNMAQYLK
  EKLNNEIVANKRESKGSSNIQETDEEDEEEEDDDDDDEGEDDGEESEETNREEEGKAKEQ
  IRNCENNCQQVTDKAFKEQRDRPEAQEQSEKKISKLDPKKLALDTSFLKVSTRPSGNQTD
  LDGSLRRVRKNDPDMKELNLNNIENIPKEMLLDFVNAMKKNKHIKTFSLANVGADENVAF
  ALANMLRENRSITTLNIESNFITGKGIVAIMRCLQFNETLTELRFHNQRHMLGHHAEMEI
  ARLLKANNTLLKMGYHFELPGPRMVVTNLLTRNQDKQRQKRQEEQKQQQLKEQKKLIAML
  ENGLGLPPGMWELLGGPKPDSRMQEFFQPPPPRPPNPQNVPFSQRSEMMKKPSQAPKYRT
  DPDSFRVVKLKRIQRKSRMPEAREPPEKTNLKDVIKTLKPVPRNRPPPLVEITPRDQLLN
  DIRHSSVAYLKPVQLPKELA
• Function: Essential for the organization of sarcomeric actin thin filaments in skeletal muscle. Increases the rate of actin polymerization.
• Tissue Specificity: Expressed in cardiac and at higher levels in skeletal muscles (at protein level).
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital myopathy	DISLSK9G	Definitive	Biomarker	[1]
Nemaline myopathy 10	DISHEAMG	Definitive	Autosomal recessive	[2]
Nemaline myopathy	DIS5IYLY	Strong	Biomarker	[3]
Severe congenital nemaline myopathy	DISJR7WP	Supportive	Autosomal recessive	[4]
Typical nemaline myopathy	DISY1645	Supportive	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Leiomodin-3 (LMOD3).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Leiomodin-3 (LMOD3).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Leiomodin-3 (LMOD3).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Leiomodin-3 (LMOD3).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Leiomodin-3 (LMOD3).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Leiomodin-3 (LMOD3).	[10]

References

• [1] Neonatal fractures as a presenting feature of LMOD3-associated congenital myopathy.Am J Med Genet A. 2017 Oct;173(10):2789-2794. doi: 10.1002/ajmg.a.38383. Epub 2017 Aug 16.
• [2] 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.
• [3] Long-term follow-up and characteristic pathological findings in severe nemaline myopathy due to LMOD3 mutations. Neuromuscul Disord. 2019 Feb;29(2):108-113. doi: 10.1016/j.nmd.2018.12.009. Epub 2018 Dec 20.
• [4] Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy. J Clin Invest. 2014 Nov;124(11):4693-708. doi: 10.1172/JCI75199. Epub 2014 Sep 24.
• [5] 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.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] 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.
• [10] 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.