Details of Drug Off-Target (DOT)

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

• DOT Name: Peripheral myelin protein 22 (PMP22)
• Synonyms: PMP-22; Growth arrest-specific protein 3; GAS-3
• Gene Name: PMP22
• Related Disease:
  Charcot-Marie-Tooth disease type 1A
  Deafness
  Hereditary neuropathy with liability to pressure palsies
  Carpal tunnel syndrome
  Charcot-Marie-Tooth disease type 1
  Charcot-Marie-Tooth disease type 1E
  Colonic neoplasm
  Colorectal adenoma
  Colorectal neoplasm
  Crohn disease
  Disorder of sexual differentiation
  Dravet syndrome
  Familial infantile myoclonic epilepsy
  Inflammatory bowel disease
  Myoclonic-astatic epilepsy
  Neuropathy, congenital hypomelinating
  Osteosarcoma
  Paralysis
  Peripheral neuropathy
  Polyneuropathy
  Schizophrenia
  Schwannoma
  Sciatic neuropathy
  Smith-Magenis syndrome
  Spastic quadriplegic cerebral palsy
  Systemic sclerosis
  Type-1/2 diabetes
  X-linked adrenal hypoplasia congenita
  Breast cancer
  Breast carcinoma
  Chronic inflammatory demyelinating polyneuropathy
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Neoplasm
  Charcot-Marie-Tooth disease type 3
  Bone osteosarcoma
  Charcot-Marie-Tooth disease type 1B
  Sensorineural hearing loss disorder
  Ulcerative colitis
• UniProt ID: PMP22_HUMAN
• Pfam ID: PF00822
• Sequence:
  MLLLLLSIIVLHVAVLVLLFVSTIVSQWIVGNGHATDLWQNCSTSSSGNVHHCFSSSPNE
  WLQSVQATMILSIIFSILSLFLFFCQLFTLTKGGRFYITGIFQILAGLCVMSAAAIYTVR
  HPEWHLNSDYSYGFAYILAWVAFPLALLSGVIYVILRKRE
• Function: Might be involved in growth regulation, and in myelinization in the peripheral nervous system.
• Reactome Pathway: EGR2 and SOX10-mediated initiation of Schwann cell myelination (R-HSA-9619665)

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot-Marie-Tooth disease type 1A	DISSRZG7	Definitive	Autosomal dominant	[1]
Deafness	DISKCLH4	Definitive	Genetic Variation	[2]
Hereditary neuropathy with liability to pressure palsies	DISY0X1V	Definitive	Autosomal dominant	[3]
Carpal tunnel syndrome	DISHQ3BE	Strong	Biomarker	[4]
Charcot-Marie-Tooth disease type 1	DIS56F9A	Strong	Biomarker	[5]
Charcot-Marie-Tooth disease type 1E	DISOA8G6	Strong	Autosomal dominant	[6]
Colonic neoplasm	DISSZ04P	Strong	Genetic Variation	[7]
Colorectal adenoma	DISTSVHM	Strong	Biomarker	[8]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[9]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[10]
Disorder of sexual differentiation	DISRMAEZ	Strong	Genetic Variation	[11]
Dravet syndrome	DISJF7LY	Strong	Biomarker	[12]
Familial infantile myoclonic epilepsy	DISELJ0F	Strong	Biomarker	[12]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[13]
Myoclonic-astatic epilepsy	DISTAVMU	Strong	Biomarker	[12]
Neuropathy, congenital hypomelinating	DISZUW4L	Strong	Genetic Variation	[14]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[15]
Paralysis	DISF9I3O	Strong	Biomarker	[16]
Peripheral neuropathy	DIS7KN5G	Strong	Biomarker	[17]
Polyneuropathy	DISB9G3W	Strong	Biomarker	[18]
Schizophrenia	DISSRV2N	Strong	Biomarker	[19]
Schwannoma	DISTTVLA	Strong	Altered Expression	[20]
Sciatic neuropathy	DISMGDKX	Strong	Biomarker	[21]
Smith-Magenis syndrome	DISG4G6X	Strong	Genetic Variation	[22]
Spastic quadriplegic cerebral palsy	DISBJRHC	Strong	Biomarker	[16]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[23]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[24]
X-linked adrenal hypoplasia congenita	DISNMXY8	Strong	Biomarker	[25]
Breast cancer	DIS7DPX1	moderate	Biomarker	[26]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[26]
Chronic inflammatory demyelinating polyneuropathy	DISNGBLD	moderate	Biomarker	[27]
Colon cancer	DISVC52G	moderate	Biomarker	[28]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[28]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[29]
Neoplasm	DISZKGEW	moderate	Biomarker	[30]
Charcot-Marie-Tooth disease type 3	DIS6DQK1	Supportive	Autosomal dominant	[31]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[15]
Charcot-Marie-Tooth disease type 1B	DISJRS1V	Limited	Biomarker	[32]
Sensorineural hearing loss disorder	DISJV45Z	Limited	Altered Expression	[33]
Ulcerative colitis	DIS8K27O	Limited	Altered Expression	[34]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Peripheral myelin protein 22 (PMP22) affects the response to substance of Etoposide.	[57]
Paclitaxel	DMLB81S	Approved	Peripheral myelin protein 22 (PMP22) decreases the response to substance of Paclitaxel.	[58]
Mitomycin	DMH0ZJE	Approved	Peripheral myelin protein 22 (PMP22) affects the response to substance of Mitomycin.	[57]

22 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 Peripheral myelin protein 22 (PMP22).	[35]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Peripheral myelin protein 22 (PMP22).	[36]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Peripheral myelin protein 22 (PMP22).	[37]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Peripheral myelin protein 22 (PMP22).	[38]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Peripheral myelin protein 22 (PMP22).	[39]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Peripheral myelin protein 22 (PMP22).	[40]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Peripheral myelin protein 22 (PMP22).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Peripheral myelin protein 22 (PMP22).	[42]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Peripheral myelin protein 22 (PMP22).	[43]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Peripheral myelin protein 22 (PMP22).	[44]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Peripheral myelin protein 22 (PMP22).	[45]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Peripheral myelin protein 22 (PMP22).	[46]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Peripheral myelin protein 22 (PMP22).	[47]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Peripheral myelin protein 22 (PMP22).	[48]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Peripheral myelin protein 22 (PMP22).	[49]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Peripheral myelin protein 22 (PMP22).	[51]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Peripheral myelin protein 22 (PMP22).	[52]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Peripheral myelin protein 22 (PMP22).	[53]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Peripheral myelin protein 22 (PMP22).	[35]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Peripheral myelin protein 22 (PMP22).	[54]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Peripheral myelin protein 22 (PMP22).	[55]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone decreases the expression of Peripheral myelin protein 22 (PMP22).	[56]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Peripheral myelin protein 22 (PMP22).	[50]

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] Charcot-Marie-Tooth type 1A disease caused by a novel Ser112Arg mutation in the PMP22 gene, coexisting with a slowly progressive hearing impairment.J Appl Genet. 2010;51(2):203-9. doi: 10.1007/BF03195729.
• [3] 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.
• [4] Clinical, neurophysiological and pathological findings of HNPP patients with 17p12 deletion: a single-centre experience.J Neurol Sci. 2014 Jun 15;341(1-2):46-50. doi: 10.1016/j.jns.2014.03.046. Epub 2014 Mar 31.
• [5] PMP22-Related neuropathies and other clinical manifestations in Chinese han patients with charcot-marie-tooth disease type 1.Muscle Nerve. 2015 Jul;52(1):69-75. doi: 10.1002/mus.24550. Epub 2015 Mar 31.
• [6] A unique point mutation in the PMP22 gene is associated with Charcot-Marie-Tooth disease and deafness. Am J Hum Genet. 1999 Jun;64(6):1580-93. doi: 10.1086/302420.
• [7] Differential expression of LEF1/TCFs family members in colonic carcinogenesis.Mol Carcinog. 2017 Nov;56(11):2372-2381. doi: 10.1002/mc.22530. Epub 2017 May 22.
• [8] Glucocorticoids promote the development of azoxymethane and dextran sulfate sodium-induced colorectal carcinoma in mice.BMC Cancer. 2019 Jan 21;19(1):94. doi: 10.1186/s12885-019-5299-8.
• [9] PPAR agonist enhances colitis-associated colorectal cancer.Eur J Pharmacol. 2019 Jan 5;842:248-254. doi: 10.1016/j.ejphar.2018.10.050. Epub 2018 Nov 2.
• [10] Evaluation of anti-inflammatory effect of silver-coated glass beads in mice with experimentally induced colitis as a new type of treatment in inflammatory bowel disease.Pharmacol Rep. 2017 Jun;69(3):386-392. doi: 10.1016/j.pharep.2017.01.003. Epub 2017 Jan 12.
• [11] Molecular basis of hereditary neuropathies.Phys Med Rehabil Clin N Am. 2001 May;12(2):277-91.
• [12] Myoclonic seizures in a patient with Charcot-Marie-tooth disease.Pediatr Neurol. 2007 Feb;36(2):118-20. doi: 10.1016/j.pediatrneurol.2006.09.006.
• [13] Faecal neutrophil elastase-antiprotease balance reflects colitis severity.Mucosal Immunol. 2020 Mar;13(2):322-333. doi: 10.1038/s41385-019-0235-4. Epub 2019 Nov 26.
• [14] Homozygous splice-site mutation c.78 +?G>A in PMP22 causes congenital hypomyelinating neuropathy.Neuropathology. 2019 Dec;39(6):441-446. doi: 10.1111/neup.12604. Epub 2019 Nov 27.
• [15] miR-200bc/429 Inhibits Osteosarcoma Cell Proliferation and Invasion by Targeting PMP22.Med Sci Monit. 2017 Feb 24;23:1001-1008. doi: 10.12659/msm.900084.
• [16] Hereditary neuropathy with liability to pressure palsies emerging during vincristine treatment.Neurology. 2002 Nov 12;59(9):1470-1. doi: 10.1212/01.wnl.0000032505.45389.94.
• [17] Role of microRNAs in senescence and its contribution to peripheral neuropathy in the arsenic exposed population of West Bengal, India. Environ Pollut. 2018 Feb;233:596-603. doi: 10.1016/j.envpol.2017.09.063. Epub 2017 Nov 5.
• [18] Absence of pathogenic mutations in CD59 in chronic inflammatory demyelinating polyradiculoneuropathy.PLoS One. 2019 Feb 22;14(2):e0212647. doi: 10.1371/journal.pone.0212647. eCollection 2019.
• [19] Schizophrenia and Hereditary Polyneuropathy: PMP22 Deletion as a Common Pathophysiological Link?.Front Psychiatry. 2019 May 2;10:270. doi: 10.3389/fpsyt.2019.00270. eCollection 2019.
• [20] Variation in SIPA1L2 is correlated with phenotype modification in Charcot- Marie- Tooth disease type 1A.Ann Neurol. 2019 Mar;85(3):316-330. doi: 10.1002/ana.25426.
• [21] Characterization of a novel peripheral nervous system myelin protein (PMP-22/SR13).J Cell Biol. 1992 Apr;117(1):225-38. doi: 10.1083/jcb.117.1.225.
• [22] Nonrecurrent PMP22-RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith-Magenis syndrome with evident peripheral neuropathy.Hum Genet. 2016 Oct;135(10):1161-74. doi: 10.1007/s00439-016-1703-5. Epub 2016 Jul 7.
• [23] Comparison of dextran-based sirolimus-eluting stents and PLA-based sirolimus-eluting stents in vitro and in vivo.J Biomed Mater Res A. 2017 Jan;105(1):301-310. doi: 10.1002/jbm.a.35898. Epub 2016 Oct 31.
• [24] Influence of comorbidities on the phenotype of patients affected by Charcot-Marie-Tooth neuropathy type 1A.Neuromuscul Disord. 2013 Nov;23(11):902-6. doi: 10.1016/j.nmd.2013.07.002. Epub 2013 Jul 23.
• [25] Three novel mutations and a de novo deletion mutation of the DAX-1 gene in patients with X-linked adrenal hypoplasia congenita.J Clin Endocrinol Metab. 1997 Nov;82(11):3835-41. doi: 10.1210/jcem.82.11.4342.
• [26] Estrogen Receptor Status Oppositely Modifies Breast Cancer Prognosis in BRCA1/BRCA2 Mutation Carriers Versus Non-Carriers.Cancers (Basel). 2019 May 28;11(6):738. doi: 10.3390/cancers11060738.
• [27] Comparison of Lewis-Sumner syndrome with chronic inflammatory demyelinating polyradiculoneuropathy patients in a tertiary care centre.Eur J Neurol. 2020 Mar;27(3):522-528. doi: 10.1111/ene.14101. Epub 2019 Oct 24.
• [28] Construing the Biochemical and Molecular Mechanism Underlying the In Vivo and In Vitro Chemotherapeutic Efficacy of Ruthenium-Baicalein Complex in Colon Cancer.Int J Biol Sci. 2019 Apr 22;15(5):1052-1071. doi: 10.7150/ijbs.31143. eCollection 2019.
• [29] Metabolic targeting of HIF-1 potentiates the therapeutic efficacy of oxaliplatin in colorectal cancer.Oncogene. 2020 Jan;39(2):414-427. doi: 10.1038/s41388-019-0999-8. Epub 2019 Sep 2.
• [30] PAR2 deficiency enhances myeloid cell-mediated immunosuppression and promotes colitis-associated tumorigenesis.Cancer Lett. 2020 Jan 28;469:437-446. doi: 10.1016/j.canlet.2019.11.015. Epub 2019 Nov 14.
• [31] Compound heterozygous deletions of PMP22 causing severe Charcot-Marie-Tooth disease of the Dejerine-Sottas disease phenotype. Am J Med Genet A. 2008 Sep 15;146A(18):2412-6. doi: 10.1002/ajmg.a.32456.
• [32] Ascorbic acid for Charcot-Marie-Tooth disease type 1A in children: a randomised, double-blind, placebo-controlled, safety and efficacy trial.Lancet Neurol. 2009 Jun;8(6):537-44. doi: 10.1016/S1474-4422(09)70108-5. Epub 2009 May 6.
• [33] Sensorineural hearing impairment in patients with Pmp22 duplication, deletion, and frameshift mutations.Otol Neurotol. 2005 May;26(3):405-14. doi: 10.1097/01.mao.0000169769.93173.df.
• [34] Suppression of miR-21 and miR-155 of macrophage by cinnamaldehyde ameliorates ulcerative colitis.Int Immunopharmacol. 2019 Feb;67:22-34. doi: 10.1016/j.intimp.2018.11.045. Epub 2018 Dec 6.
• [35] 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.
• [36] 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.
• [37] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [38] 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.
• [39] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [40] 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.
• [41] Role of microRNAs in senescence and its contribution to peripheral neuropathy in the arsenic exposed population of West Bengal, India. Environ Pollut. 2018 Feb;233:596-603. doi: 10.1016/j.envpol.2017.09.063. Epub 2017 Nov 5.
• [42] 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.
• [43] 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.
• [44] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [45] Decitabine up-regulates S100A2 expression and synergizes with IFN-gamma to kill uveal melanoma cells. Clin Cancer Res. 2007 Sep 1;13(17):5219-25. doi: 10.1158/1078-0432.CCR-07-0816.
• [46] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [47] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [48] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [49] Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease. Nat Med. 2004 Apr;10(4):396-401. doi: 10.1038/nm1023. Epub 2004 Mar 21.
• [50] 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.
• [51] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [52] 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.
• [53] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [54] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [55] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [56] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.
• [57] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [58] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.