Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS9IBNE)

• DOT Name: EF-hand domain-containing protein 1 (EFHC1)
• Synonyms: Myoclonin-1
• Gene Name: EFHC1
• Related Disease:
  Absence epilepsy
  Absence seizure
  Asthma
  Atopic dermatitis
  Benign neonatal seizures
  Epilepsy syndrome
  Peripheral arterial disease
  Epilepsy with generalized tonic-clonic seizures
  Epilepsy, idiopathic generalized
  Juvenile myoclonic epilepsy
  Migraine disorder
  Epilepsy
• UniProt ID: EFHC1_HUMAN
• PDB ID: 7UNG; 8J07
• Pfam ID: PF06565
• Sequence:
  MVSNPVHGLPFLPGTSFKDSTKTAFHRSQTLSYRNGYAIVRRPTVGIGGDRLQFNQLSQA
  ELDELASKAPVLTYGQPKQAPPADFIPAHVAFDKKVLKFDAYFQEDVPMSTEEQYRIRQV
  NIYYYLEDDSMSVIEPVVENSGILQGKLIKRQRLAKNDRGDHYHWKDLNRGINITIYGKT
  FRVVDCDQFTQVFLESQGIELNPPEKMALDPYTELRKQPLRKYVTPSDFDQLKQFLTFDK
  QVLRFYAIWDDTDSMYGECRTYIIHYYLMDDTVEIREVHERNDGRDPFPLLMNRQRVPKV
  LVENAKNFPQCVLEISDQEVLEWYTAKDFIVGKSLTILGRTFFIYDCDPFTRRYYKEKFG
  ITDLPRIDVSKREPPPVKQELPPYNGFGLVEDSAQNCFALIPKAPKKDVIKMLVNDNKVL
  RYLAVLESPIPEDKDRRFVFSYFLATDMISIFEPPVRNSGIIGGKYLGRTKVVKPYSTVD
  NPVYYGPSDFFIGAVIEVFGHRFIILDTDEYVLKYMESNAAQYSPEALASIQNHVRKREA
  PAPEAESKQTEKDPGVQELEALIDTIQKQLKDHSCKDNIREAFQIYDKEASGYVDRDMFF
  KICESLNVPVDDSLVKELIRMCSHGEGKINYYNFVRAFSN
• Function: Microtubule-associated protein which regulates cell division and neuronal migration during cortical development. Necessary for mitotic spindle organization. Necessary for radial and tangential cell migration during brain development, possibly acting as a regulator of cell morphology and process formation during migration. May enhance calcium influx through CACNA1E and stimulate programmed cell death. Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.
• Tissue Specificity: Widely expressed. Not detected in lymphocytes.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Absence epilepsy	DISJPOUD	Strong	Genetic Variation	[1]
Absence seizure	DIS4709R	Strong	Genetic Variation	[1]
Asthma	DISW9QNS	Strong	Genetic Variation	[2]
Atopic dermatitis	DISTCP41	Strong	Genetic Variation	[2]
Benign neonatal seizures	DISWNBHF	Strong	Biomarker	[3]
Epilepsy syndrome	DISLYXJ3	Strong	Genetic Variation	[4]
Peripheral arterial disease	DIS78WFB	Strong	Genetic Variation	[5]
Epilepsy with generalized tonic-clonic seizures	DISMG0FL	moderate	Genetic Variation	[6]
Epilepsy, idiopathic generalized	DISODZC9	moderate	Genetic Variation	[7]
Juvenile myoclonic epilepsy	DISYXV1N	Limited	Autosomal dominant	[8]
Migraine disorder	DISFCQTG	Limited	Biomarker	[9]
Epilepsy	DISBB28L	Refuted	Autosomal dominant	[10]

11 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 EF-hand domain-containing protein 1 (EFHC1).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of EF-hand domain-containing protein 1 (EFHC1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of EF-hand domain-containing protein 1 (EFHC1).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of EF-hand domain-containing protein 1 (EFHC1).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of EF-hand domain-containing protein 1 (EFHC1).	[15]
Selenium	DM25CGV	Approved	Selenium decreases the expression of EF-hand domain-containing protein 1 (EFHC1).	[16]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of EF-hand domain-containing protein 1 (EFHC1).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of EF-hand domain-containing protein 1 (EFHC1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of EF-hand domain-containing protein 1 (EFHC1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of EF-hand domain-containing protein 1 (EFHC1).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of EF-hand domain-containing protein 1 (EFHC1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of EF-hand domain-containing protein 1 (EFHC1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of EF-hand domain-containing protein 1 (EFHC1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of EF-hand domain-containing protein 1 (EFHC1).	[17]

References

• [1] Progress in mapping human epilepsy genes.Epilepsia. 1994;35 Suppl 1:S29-40. doi: 10.1111/j.1528-1157.1994.tb05926.x.
• [2] Meta-analysis identifies seven susceptibility loci involved in the atopic march.Nat Commun. 2015 Nov 6;6:8804. doi: 10.1038/ncomms9804.
• [3] The genetics of idiopathic generalized epilepsy: implications for the understanding of its aetiology.Mol Med Today. 1996 Apr;2(4):173-80. doi: 10.1016/1357-4310(96)88793-4.
• [4] Idiopathic generalized epilepsy phenotypes associated with different EFHC1 mutations.Neurology. 2006 Dec 12;67(11):2029-31. doi: 10.1212/01.wnl.0000250254.67042.1b.
• [5] Genetic Variants in the Bone Morphogenic Protein Gene Family Modify the Association between Residential Exposure to Traffic and Peripheral Arterial Disease.PLoS One. 2016 Apr 15;11(4):e0152670. doi: 10.1371/journal.pone.0152670. eCollection 2016.
• [6] The genetics of idiopathic generalized epilepsies of adolescent onset: differences between juvenile myoclonic epilepsy and epilepsy with random grand mal and with awakening grand mal.Neurology. 1995 May;45(5):942-6. doi: 10.1212/wnl.45.5.942.
• [7] Pathogenic EFHC1 mutations are tolerated in healthy individuals dependent on reported ancestry.Epilepsia. 2015 Feb;56(2):188-94. doi: 10.1111/epi.12864. Epub 2014 Dec 8.
• [8] Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nat Genet. 2004 Aug;36(8):842-9. doi: 10.1038/ng1393. Epub 2004 Jul 18.
• [9] Exclusion of the juvenile myoclonic epilepsy gene EFHC1 as the cause of migraine on chromosome 6, but association to two rare polymorphisms in MEP1A and RHAG.Neurosci Lett. 2006 Mar 27;396(2):137-42. doi: 10.1016/j.neulet.2005.11.039. Epub 2005 Dec 27.
• [10] 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.
• [11] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [12] 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.
• [13] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [17] 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.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] 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.
• [20] 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.
• [21] 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.