Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEMVFX7)

• DOT Name: Receptor expression-enhancing protein 1 (REEP1)
• Synonyms: Spastic paraplegia 31 protein
• Gene Name: REEP1
• Related Disease:
  Hereditary spastic paraplegia 31
  Nervous system disease
  Acquired partial lipodystrophy
  Cardiomyopathy
  Hereditary neuropathy with liability to pressure palsies
  Hereditary spastic paraplegia
  Hereditary spastic paraplegia 10
  Hereditary spastic paraplegia 3A
  Hereditary spastic paraplegia 4
  Lipodystrophy
  Nerve compression syndrome
  Neuronopathy, distal hereditary motor, type 5
  Neuronopathy, distal hereditary motor, type 5B
  Peripheral neuropathy
  Polyneuropathy
  Restless legs syndrome
  Vascular purpura
  Atrial fibrillation
  Familial atrial fibrillation
  Hereditary spastic paraplegia 7
  Neuronopathy, distal hereditary motor, type 5A
  Intellectual disability
  Spinal muscular atrophy, distal, autosomal recessive, 6
• UniProt ID: REEP1_HUMAN
• Pfam ID: PF03134
• Sequence:
  MVSWIISRLVVLIFGTLYPAYYSYKAVKSKDIKEYVKWMMYWIIFALFTTAETFTDIFLC
  WFPFYYELKIAFVAWLLSPYTKGSSLLYRKFVHPTLSSKEKEIDDCLVQAKDRSYDALVH
  FGKRGLNVAATAAVMAASKGQGALSERLRSFSMQDLTTIRGDGAPAPSGPPPPGSGRASG
  KHGQPKMSRSASESASSSGTA
• Function: Required for endoplasmic reticulum (ER) network formation, shaping and remodeling; it links ER tubules to the cytoskeleton. May also enhance the cell surface expression of odorant receptors. May play a role in long-term axonal maintenance.
• Tissue Specificity: Expressed in circumvallate papillae and testis.
• Reactome Pathway: Expression and translocation of olfactory receptors (R-HSA-9752946)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary spastic paraplegia 31	DISZZWA2	Definitive	Autosomal dominant	[1]
Nervous system disease	DISJ7GGT	Definitive	Genetic Variation	[2]
Acquired partial lipodystrophy	DISWXX4G	Strong	Biomarker	[3]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[4]
Hereditary neuropathy with liability to pressure palsies	DISY0X1V	Strong	Genetic Variation	[5]
Hereditary spastic paraplegia	DISGZQV1	Strong	Biomarker	[5]
Hereditary spastic paraplegia 10	DISYFO3L	Strong	Biomarker	[6]
Hereditary spastic paraplegia 3A	DISWGEU6	Strong	Genetic Variation	[7]
Hereditary spastic paraplegia 4	DISFUYL2	Strong	Genetic Variation	[7]
Lipodystrophy	DIS3SGVD	Strong	Genetic Variation	[3]
Nerve compression syndrome	DIS93JJO	Strong	Genetic Variation	[5]
Neuronopathy, distal hereditary motor, type 5	DISTSHF6	Strong	GermlineCausalMutation	[4]
Neuronopathy, distal hereditary motor, type 5B	DISFQQ5I	Strong	Autosomal dominant	[8]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[5]
Polyneuropathy	DISB9G3W	Strong	Genetic Variation	[5]
Restless legs syndrome	DISNWY00	Strong	Biomarker	[9]
Vascular purpura	DIS6ZZMF	Strong	Biomarker	[5]
Atrial fibrillation	DIS15W6U	moderate	Biomarker	[10]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[10]
Hereditary spastic paraplegia 7	DIS4A678	moderate	Biomarker	[11]
Neuronopathy, distal hereditary motor, type 5A	DISD3JAD	Supportive	Autosomal dominant	[4]
Intellectual disability	DISMBNXP	Limited	Biomarker	[12]
Spinal muscular atrophy, distal, autosomal recessive, 6	DIS70FM2	Limited	Autosomal recessive	[1]

3 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 Receptor expression-enhancing protein 1 (REEP1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Receptor expression-enhancing protein 1 (REEP1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Receptor expression-enhancing protein 1 (REEP1).	[24]

10 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 Receptor expression-enhancing protein 1 (REEP1).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Receptor expression-enhancing protein 1 (REEP1).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Receptor expression-enhancing protein 1 (REEP1).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Receptor expression-enhancing protein 1 (REEP1).	[17]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Receptor expression-enhancing protein 1 (REEP1).	[18]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Receptor expression-enhancing protein 1 (REEP1).	[19]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Receptor expression-enhancing protein 1 (REEP1).	[20]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Receptor expression-enhancing protein 1 (REEP1).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Receptor expression-enhancing protein 1 (REEP1).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Receptor expression-enhancing protein 1 (REEP1).	[25]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Spastic paraplegia type 31: A novel REEP1 splice site donor variant and expansion of the phenotype variability.Parkinsonism Relat Disord. 2018 Jan;46:79-83. doi: 10.1016/j.parkreldis.2017.10.012. Epub 2017 Oct 21.
• [3] Reep1 null mice reveal a converging role for hereditary spastic paraplegia proteins in lipid droplet regulation.Hum Mol Genet. 2016 Dec 1;25(23):5111-5125. doi: 10.1093/hmg/ddw315.
• [4] Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V. Am J Hum Genet. 2012 Jul 13;91(1):139-45. doi: 10.1016/j.ajhg.2012.05.007. Epub 2012 Jun 14.
• [5] Peripheral neuropathy in hereditary spastic paraplegia caused by REEP1 variants.J Neurol. 2019 Mar;266(3):735-744. doi: 10.1007/s00415-019-09196-1. Epub 2019 Jan 12.
• [6] De novo REEP2 missense mutation in pure hereditary spastic paraplegia.Ann Clin Transl Neurol. 2017 Apr 11;4(5):347-350. doi: 10.1002/acn3.404. eCollection 2017 May.
• [7] Molecular spectrum of the SPAST, ATL1 and REEP1 gene mutations associated with the most common hereditary spastic paraplegias in a group of Polish patients.J Neurol Sci. 2015 Dec 15;359(1-2):35-9. doi: 10.1016/j.jns.2015.10.030. Epub 2015 Oct 17.
• [8] REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain. 2008 Apr;131(Pt 4):1078-86. doi: 10.1093/brain/awn026. Epub 2008 Mar 5.
• [9] ATL1 and REEP1 mutations in hereditary and sporadic upper motor neuron syndromes.J Neurol. 2013 Mar;260(3):869-75. doi: 10.1007/s00415-012-6723-z. Epub 2012 Oct 30.
• [10] Biobank-driven genomic discovery yields new insight into atrial fibrillation biology.Nat Genet. 2018 Sep;50(9):1234-1239. doi: 10.1038/s41588-018-0171-3. Epub 2018 Jul 30.
• [11] Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy.Brain. 2012 Oct;135(Pt 10):2980-93. doi: 10.1093/brain/aws240.
• [12] Contribution of SNP arrays in diagnosis of deletion 2p11.2-p12.Gene. 2012 Jan 15;492(1):315-8. doi: 10.1016/j.gene.2011.10.035. Epub 2011 Oct 28.
• [13] 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.
• [14] 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.
• [15] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [16] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [17] 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.
• [18] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] 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.
• [21] 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.
• [22] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [23] 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.
• [24] 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.
• [25] 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.