Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJU4IAG)

• DOT Name: Laforin (EPM2A)
• Synonyms: EC 3.1.3.-; EC 3.1.3.16; EC 3.1.3.48; Glucan phosphatase; Glycogen phosphatase; Lafora PTPase; LAFPTPase
• Gene Name: EPM2A
• Related Disease:
  Lafora disease
  Action myoclonus-renal failure syndrome
  Advanced cancer
  Carbohydrate metabolism disease
  Childhood epilepsy with centrotemporal spikes
  CLN2 Batten disease
  Cognitive impairment
  Dementia
  Dentatorubral-pallidoluysian atrophy
  Dravet syndrome
  Epilepsy
  Lymphoma
  Narcolepsy
  Progressive myoclonus epilepsy
  Schizophrenia
  Adult lymphoma
  Neoplasm
  Pediatric lymphoma
  Unverricht-Lundborg syndrome
• UniProt ID: EPM2A_HUMAN
• PDB ID: 4R30; 4RKK
• EC Number: 3.1.3.-; 3.1.3.16; 3.1.3.48
• Pfam ID: PF00686 ; PF00782
• Sequence:
  MRFRFGVVVPPAVAGARPELLVVGSRPELGRWEPRGAVRLRPAGTAAGDGALALQEPGLW
  LGEVELAAEEAAQDGAEPGRVDTFWYKFLKREPGGELSWEGNGPHHDRCCTYNENNLVDG
  VYCLPIGHWIEATGHTNEMKHTTDFYFNIAGHQAMHYSRILPNIWLGSCPRQVEHVTIKL
  KHELGITAVMNFQTEWDIVQNSSGCNRYPEPMTPDTMIKLYREEGLAYIWMPTPDMSTEG
  RVQMLPQAVCLLHALLEKGHIVYVHCNAGVGRSTAAVCGWLQYVMGWNLRKVQYFLMAKR
  PAVYIDEEALARAQEDFFQKFGKVRSSVCSL
• Function: Plays an important role in preventing glycogen hyperphosphorylation and the formation of insoluble aggregates, via its activity as glycogen phosphatase, and by promoting the ubiquitination of proteins involved in glycogen metabolism via its interaction with the E3 ubiquitin ligase NHLRC1/malin. Shows strong phosphatase activity towards complex carbohydrates in vitro, avoiding glycogen hyperphosphorylation which is associated with reduced branching and formation of insoluble aggregates. Dephosphorylates phosphotyrosine and synthetic substrates, such as para-nitrophenylphosphate (pNPP), and has low activity with phosphoserine and phosphothreonine substrates (in vitro). Has been shown to dephosphorylate MAPT. Forms a complex with NHLRC1/malin and HSP70, which suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Acts as a scaffold protein to facilitate PPP1R3C/PTG ubiquitination by NHLRC1/malin. Also promotes proteasome-independent protein degradation through the macroautophagy pathway ; [Isoform 2]: Does not bind to glycogen. Lacks phosphatase activity and might function as a dominant-negative regulator for the phosphatase activity of isoform 1 and isoform 7 ; [Isoform 7]: Has phosphatase activity (in vitro).
• Tissue Specificity: Expressed in heart, skeletal muscle, kidney, pancreas and brain. Isoform 4 is also expressed in the placenta.
• Reactome Pathway:
  Myoclonic epilepsy of Lafora (R-HSA-3785653)
  Glycogen synthesis (R-HSA-3322077)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lafora disease	DIS83JHH	Definitive	Autosomal recessive	[1]
Action myoclonus-renal failure syndrome	DISI2BZN	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Carbohydrate metabolism disease	DISWRYYA	Strong	Biomarker	[4]
Childhood epilepsy with centrotemporal spikes	DISKT2L5	Strong	CausalMutation	[5]
CLN2 Batten disease	DISZC5YB	Strong	Genetic Variation	[6]
Cognitive impairment	DISH2ERD	Strong	Genetic Variation	[7]
Dementia	DISXL1WY	Strong	Genetic Variation	[7]
Dentatorubral-pallidoluysian atrophy	DISHWE0K	Strong	Biomarker	[2]
Dravet syndrome	DISJF7LY	Strong	Biomarker	[8]
Epilepsy	DISBB28L	Strong	Biomarker	[9]
Lymphoma	DISN6V4S	Strong	Altered Expression	[10]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[11]
Progressive myoclonus epilepsy	DISAMCNS	Strong	Genetic Variation	[12]
Schizophrenia	DISSRV2N	Strong	Biomarker	[13]
Adult lymphoma	DISK8IZR	Disputed	Altered Expression	[10]
Neoplasm	DISZKGEW	Disputed	Biomarker	[10]
Pediatric lymphoma	DIS51BK2	Disputed	Altered Expression	[10]
Unverricht-Lundborg syndrome	DISG4WLX	Limited	Genetic Variation	[8]

1 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 Laforin (EPM2A).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Laforin (EPM2A).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Laforin (EPM2A).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Laforin (EPM2A).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Laforin (EPM2A).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Laforin (EPM2A).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Laforin (EPM2A).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Laforin (EPM2A).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Laforin (EPM2A).	[22]

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] A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet. 2015 Jan;47(1):39-46. doi: 10.1038/ng.3144. Epub 2014 Nov 17.
• [3] Laforin confers cancer resistance to energy deprivation-induced apoptosis.Cancer Res. 2008 Jun 1;68(11):4039-44. doi: 10.1158/0008-5472.CAN-07-6314.
• [4] Lafora disease: epidemiology, pathophysiology and management.CNS Drugs. 2010 Jul;24(7):549-61. doi: 10.2165/11319250-000000000-00000.
• [5] Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.Eur J Hum Genet. 2018 Feb;26(2):258-264. doi: 10.1038/s41431-017-0034-x. Epub 2018 Jan 22.
• [6] Advances in the genetics of progressive myoclonus epilepsy.Am J Med Genet. 2001 Summer;106(2):129-38. doi: 10.1002/ajmg.1575.
• [7] Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype.Hum Mol Genet. 2002 May 15;11(11):1263-71. doi: 10.1093/hmg/11.11.1263.
• [8] Debate: Does genetic information in humans help us treat patients PRO--genetic information in humans helps us treat patients. CON--genetic information does not help at all. Epilepsia. 2008 Dec;49 Suppl 9:13-24.
• [9] Malin and laforin are essential components of a protein complex that protects cells from thermal stress.J Cell Sci. 2011 Jul 1;124(Pt 13):2277-86. doi: 10.1242/jcs.082800. Epub 2011 Jun 7.
• [10] Epm2a suppresses tumor growth in an immunocompromised host by inhibiting Wnt signaling.Cancer Cell. 2006 Sep;10(3):179-90. doi: 10.1016/j.ccr.2006.08.008.
• [11] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [12] Lafora disease.Epileptic Disord. 2016 Sep 1;18(S2):38-62. doi: 10.1684/epd.2016.0842.
• [13] PDE7B, NMBR and EPM2A Variants and Schizophrenia: A Case-Control and Pharmacogenetics Study.Neuropsychobiology. 2016;73(3):160-8. doi: 10.1159/000445295. Epub 2016 Apr 20.
• [14] 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.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] 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.
• [17] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [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.