Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ7AT38)

• DOT Name: Piezo-type mechanosensitive ion channel component 2 (PIEZO2)
• Synonyms: Protein FAM38B
• Gene Name: PIEZO2
• Related Disease:
  Arthrogryposis, distal, with impaired proprioception and touch
  Gordon syndrome
  Advanced cancer
  Arthrogryposis
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Glioma
  Irritable bowel syndrome
  Neoplasm
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Pseudohypoaldosteronism type 2
  Respiratory failure
  Sheldon-hall syndrome
  Skin pigmentation disorder
  Urinary bladder cancer
  Urinary bladder neoplasm
  Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome
  Connective tissue disorder
  Marden-Walker syndrome
  Distal arthrogryposis
• UniProt ID: PIEZ2_HUMAN
• Pfam ID: PF15917 ; PF12166
• Sequence:
  MASEVVCGLIFRLLLPICLAVACAFRYNGLSFVYLIYLLLIPLFSEPTKTTMQGHTGRLL
  KSLCFISLSFLLLHIIFHITLVSLEAQHRIAPGYNCSTWEKTFRQIGFESLKGADAGNGI
  RVFVPDIGMFIASLTIWLLCRNIVQKPVTDEAAQSNPEFENEELAEGEKIDSEEALIYEE
  DFNGGDGVEGELEESTKLKMFRRLASVASKLKEFIGNMITTAGKVVVTILLGSSGMMLPS
  LTSSVYFFVFLGLCTWWSWCRTFDPLLFSCLCVLLAIFTAGHLIGLYLYQFQFFQEAVPP
  NDYYARLFGIKSVIQTDCSSTWKIIVNPDLSWYHHANPILLLVMYYTLATLIRIWLQEPL
  VQDEGTKEEDKALACSPIQITAGRRRSLWYATHYPTDERKLLSMTQDDYKPSDGLLVTVN
  GNPVDYHTIHPSLPMENGPGKADLYSTPQYRWEPSDESSEKREEEEEEKEEFEEERSREE
  KRSIKVHAMVSVFQFIMKQSYICALIAMMAWSITYHSWLTFVLLIWSCTLWMIRNRRKYA
  MISSPFMVVYGNLLLILQYIWSFELPEIKKVPGFLEKKEPGELASKILFTITFWLLLRQH
  LTEQKALQEKEALLSEVKIGSQENEEKDEELQDIQVEGEPKEEEEEEAKEEKQERKKVEQ
  EEAEEEDEQDIMKVLGNLVVAMFIKYWIYVCGGMFFFVSFEGKIVMYKIIYMVLFLFCVA
  LYQVHYEWWRKILKYFWMSVVIYTMLVLIFIYTYQFENFPGLWQNMTGLKKEKLEDLGLK
  QFTVAELFTRIFIPTSFLLVCILHLHYFHDRFLELTDLKSIPSKEDNTIYRLAHPEGSLP
  DLTMMHLTASLEKPEVRKLAEPGEEKLEGYSEKAQKGDLGKDSEESEEDGEEEEESEEEE
  ETSDLRNKWHLVIDRLTVLFLKFLEYFHKLQVFMWWILELHIIKIVSSYIIWVSVKEVSL
  FNYVFLISWAFALPYAKLRRLASSVCTVWTCVIIVCKMLYQLQTIKPENFSVNCSLPNEN
  QTNIPFNELNKSLLYSAPIDPTEWVGLRKSSPLLVYLRNNLLMLAILAFEVTIYRHQEYY
  RGRNNLTAPVSRTIFHDITRLHLDDGLINCAKYFINYFFYKFGLETCFLMSVNVIGQRMD
  FYAMIHACWLIAVLYRRRRKAIAEIWPKYCCFLACIITFQYFICIGIPPAPCRDYPWRFK
  GASFNDNIIKWLYFPDFIVRPNPVFLVYDFMLLLCASLQRQIFEDENKAAVRIMAGDNVE
  ICMNLDAASFSQHNPVPDFIHCRSYLDMSKVIIFSYLFWFVLTIIFITGTTRISIFCMGY
  LVACFYFLLFGGDLLLKPIKSILRYWDWLIAYNVFVITMKNILSIGACGYIGTLVHNSCW
  LIQAFSLACTVKGYQMPAANSPCTLPSGEAGIIWDSICFAFLLLQRRVFMSYYFLHVVAD
  IKASQILASRGAELFQATIVKAVKARIEEEKKSMDQLKRQMDRIKARQQKYKKGKERMLS
  LTQEPGEGQDMQKLSEEDDEREADKQKAKGKKKQWWRPWVDHASMVRSGDYYLFETDSEE
  EEEEELKKEDEEPPRRSAFQFVYQAWITDPKTALRQRHKEKKRSAREERKRRRKGSKEGP
  VEWEDREDEPIKKKSDGPDNIIKRIFNILKFTWVLFLATVDSFTTWLNSISREHIDISTV
  LRIERCMLTREIKKGNVPTRESIHMYYQNHIMNLSRESGLDTIDEHPGAASGAQTAHRMD
  SLDSHDSISSEPTQCTMLYSRQGTTETIEEVEAEQEEEAGSTAPEPREAKEYEATGYDVG
  AMGAEEASLTPEEELTQFSTLDGDVEAPPSYSKAVSFEHLSFGSQDDSAGKNRMAVSPDD
  SRTDKLGSSILPPLTHELTASELLLKKMFHDDELEESEKFYVGQPRFLLLFYAMYNTLVA
  RSEMVCYFVIILNHMVSASMITLLLPILIFLWAMLSVPRPSRRFWMMAIVYTEVAIVVKY
  FFQFGFFPWNKNVEVNKDKPYHPPNIIGVEKKEGYVLYDLIQLLALFFHRSILKCHGLWD
  EDDMTESGMAREESDDELSLGHGRRDSSDSLKSINLAASVESVHVTFPEQQTAVRRKRSG
  SSSEPSQRSSFSSNRSQRGSTSTRNSSQKGSSVLSIKQKGKRELYMEKLQEHLIKAKAFT
  IKKTLEIYVPIKQFFYNLIHPEYSAVTDVYVLMFLADTVDFIIIVFGFWAFGKHSAAADI
  TSSLSEDQVPGPFLVMVLIQFGTMVVDRALYLRKTVLGKVIFQVILVFGIHFWMFFILPG
  VTERKFSQNLVAQLWYFVKCVYFGLSAYQIRCGYPTRVLGNFLTKSYNYVNLFLFQGFRL
  VPFLTELRAVMDWVWTDTTLSLSSWICVEDIYAHIFILKCWRESEKRYPQPRGQKKKKVV
  KYGMGGMIIVLLICIVWFPLLFMSLIKSVAGVINQPLDVSVTITLGGYQPIFTMSAQQSQ
  LKVMDQQSFNKFIQAFSRDTGAMQFLENYEKEDITVAELEGNSNSLWTISPPSKQKMIHE
  LLDPNSSFSVVFSWSIQRNLSLGAKSEIATDKLSFPLKNITRKNIAKMIAGNSTESSKTP
  VTIEKIYPYYVKAPSDSNSKPIKQLLSENNFMDITIILSRDNTTKYNSEWWVLNLTGNRI
  YNPNSQALELVVFNDKVSPPSLGFLAGYGIMGLYASVVLVIGKFVREFFSGISHSIMFEE
  LPNVDRILKLCTDIFLVRETGELELEEDLYAKLIFLYRSPETMIKWTREKTN
• Function: Pore-forming subunit of a mechanosensitive non-specific cation channel required for rapidly adapting mechanically activated (MA) currents and has a key role in sensing touch and tactile pain. Required for Merkel-cell mechanotransduction. Plays a major role in light-touch mechanosensation.

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthrogryposis, distal, with impaired proprioception and touch	DISKYE23	Definitive	Autosomal recessive	[1]
Gordon syndrome	DISVMP0Y	Definitive	Autosomal dominant	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Arthrogryposis	DISC81CM	Strong	CausalMutation	[4]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[6]
Irritable bowel syndrome	DIS27206	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[9]
Pseudohypoaldosteronism type 2	DISFTCHO	Strong	Genetic Variation	[10]
Respiratory failure	DISVMYJO	Strong	Genetic Variation	[11]
Sheldon-hall syndrome	DISOCVMC	Strong	GermlineCausalMutation	[12]
Skin pigmentation disorder	DIS3BXY0	Strong	Altered Expression	[13]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[5]
Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome	DISBCS1Y	Moderate	Autosomal dominant	[14]
Connective tissue disorder	DISKXBS3	Moderate	Autosomal recessive	[15]
Marden-Walker syndrome	DISUAMD9	Moderate	Autosomal recessive	[15]
Distal arthrogryposis	DIS3QIEL	Limited	Genetic Variation	[10]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Piezo-type mechanosensitive ion channel component 2 (PIEZO2) increases the Metabolic disorder ADR of Chlorothiazide.	[27]

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 Piezo-type mechanosensitive ion channel component 2 (PIEZO2).	[16]

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 Piezo-type mechanosensitive ion channel component 2 (PIEZO2).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Piezo-type mechanosensitive ion channel component 2 (PIEZO2).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Piezo-type mechanosensitive ion channel component 2 (PIEZO2).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Piezo-type mechanosensitive ion channel component 2 (PIEZO2).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Piezo-type mechanosensitive ion channel component 2 (PIEZO2).	[21]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Piezo-type mechanosensitive ion channel component 2 (PIEZO2).	[22]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Piezo-type mechanosensitive ion channel component 2 (PIEZO2).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Piezo-type mechanosensitive ion channel component 2 (PIEZO2).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Piezo-type mechanosensitive ion channel component 2 (PIEZO2).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Piezo-type mechanosensitive ion channel component 2 (PIEZO2).	[26]

References

• [1] The Role of PIEZO2 in Human Mechanosensation. N Engl J Med. 2016 Oct 6;375(14):1355-1364. doi: 10.1056/NEJMoa1602812. Epub 2016 Sep 21.
• [2] Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. Am J Hum Genet. 2014 May 1;94(5):734-44. doi: 10.1016/j.ajhg.2014.03.015. Epub 2014 Apr 10.
• [3] Five miRNAs-mediated PIEZO2 downregulation, accompanied with activation of Hedgehog signaling pathway, predicts poor prognosis of breast cancer.Aging (Albany NY). 2019 May 6;11(9):2628-2652. doi: 10.18632/aging.101934.
• [4] The genomic and clinical landscape of fetal akinesia.Genet Med. 2020 Mar;22(3):511-523. doi: 10.1038/s41436-019-0680-1. Epub 2019 Nov 4.
• [5] The increased expression of Piezo1 and Piezo2 ion channels in human and mouse bladder carcinoma.Adv Clin Exp Med. 2018 Aug;27(8):1025-1031. doi: 10.17219/acem/71080.
• [6] Piezo2 protein: A novel regulator of tumor angiogenesis and hyperpermeability.Oncotarget. 2016 Jul 12;7(28):44630-44643. doi: 10.18632/oncotarget.10134.
• [7] Piezo2: A Candidate Biomarker for Visceral Hypersensitivity in Irritable Bowel Syndrome?.J Neurogastroenterol Motil. 2017 Jul 30;23(3):453-463. doi: 10.5056/jnm16114.
• [8] Susceptible gene of stasis-stagnation constitution from genome-wide association study related to cardiovascular disturbance and possible regulated traditional Chinese medicine.BMC Complement Altern Med. 2015 Jul 14;15:229. doi: 10.1186/s12906-015-0761-x.
• [9] The 18p11.22 locus is associated with never smoker non-small cell lung cancer susceptibility in Korean populations.Hum Genet. 2012 Mar;131(3):365-72. doi: 10.1007/s00439-011-1080-z. Epub 2011 Aug 25.
• [10] Mutations in PIEZO2 contribute to Gordon syndrome, Marden-Walker syndrome and distal arthrogryposis: A bioinformatics analysis of mechanisms.Exp Ther Med. 2019 May;17(5):3518-3524. doi: 10.3892/etm.2019.7381. Epub 2019 Mar 13.
• [11] A novel nonsense PIEZO2 mutation in a family with scoliosis and proprioceptive defect.Neuromuscul Disord. 2019 Jan;29(1):75-79. doi: 10.1016/j.nmd.2018.10.005. Epub 2018 Nov 8.
• [12] Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis. Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4667-72. doi: 10.1073/pnas.1221400110. Epub 2013 Mar 4.
• [13] Cutaneous pigmentation modulates skin sensitivity via tyrosinase-dependent dopaminergic signalling.Sci Rep. 2017 Aug 23;7(1):9181. doi: 10.1038/s41598-017-09682-4.
• [14] 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.
• [15] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [20] 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.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] 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.
• [23] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [24] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [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.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.