Details of Drug Off-Target (DOT)

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

• DOT Name: Unconventional myosin-VIIa (MYO7A)
• Gene Name: MYO7A
• Related Disease:
  Autosomal dominant nonsyndromic hearing loss 12
  Autosomal recessive nonsyndromic hearing loss 2
  Metastatic malignant neoplasm
  Nonsyndromic genetic hearing loss
  Usher syndrome type 1
  Usher syndrome type 1B
  Auditory neuropathy
  Autosomal dominant nonsyndromic hearing loss 11
  Autosomal dominant nonsyndromic hearing loss 13
  Autosomal dominant nonsyndromic hearing loss 9
  Bardet biedl syndrome
  Blindness
  Deafness
  Lung cancer
  Lung carcinoma
  Melanoma
  Usher syndrome
  Usher syndrome type 2D
  Usher syndrome type 3
  Age-related macular degeneration
  Ear malformation
  Retinopathy
  Autosomal dominant nonsyndromic hearing loss
  Hearing loss, autosomal recessive
  Usher syndrome type 2
  Leber congenital amaurosis
  Retinitis pigmentosa
  Severe early-childhood-onset retinal dystrophy
• UniProt ID: MYO7A_HUMAN
• PDB ID: 5MV9
• Pfam ID: PF00373 ; PF00612 ; PF00063 ; PF00784
• Sequence:
  MVILQQGDHVWMDLRLGQEFDVPIGAVVKLCDSGQVQVVDDEDNEHWISPQNATHIKPMH
  PTSVHGVEDMIRLGDLNEAGILRNLLIRYRDHLIYTYTGSILVAVNPYQLLSIYSPEHIR
  QYTNKKIGEMPPHIFAIADNCYFNMKRNSRDQCCIISGESGAGKTESTKLILQFLAAISG
  QHSWIEQQVLEATPILEAFGNAKTIRNDNSSRFGKYIDIHFNKRGAIEGAKIEQYLLEKS
  RVCRQALDERNYHVFYCMLEGMSEDQKKKLGLGQASDYNYLAMGNCITCEGRVDSQEYAN
  IRSAMKVLMFTDTENWEISKLLAAILHLGNLQYEARTFENLDACEVLFSPSLATAASLLE
  VNPPDLMSCLTSRTLITRGETVSTPLSREQALDVRDAFVKGIYGRLFVWIVDKINAAIYK
  PPSQDVKNSRRSIGLLDIFGFENFAVNSFEQLCINFANEHLQQFFVRHVFKLEQEEYDLE
  SIDWLHIEFTDNQDALDMIANKPMNIISLIDEESKFPKGTDTTMLHKLNSQHKLNANYIP
  PKNNHETQFGINHFAGIVYYETQGFLEKNRDTLHGDIIQLVHSSRNKFIKQIFQADVAMG
  AETRKRSPTLSSQFKRSLELLMRTLGACQPFFVRCIKPNEFKKPMLFDRHLCVRQLRYSG
  MMETIRIRRAGYPIRYSFVEFVERYRVLLPGVKPAYKQGDLRGTCQRMAEAVLGTHDDWQ
  IGKTKIFLKDHHDMLLEVERDKAITDRVILLQKVIRGFKDRSNFLKLKNAATLIQRHWRG
  HNCRKNYGLMRLGFLRLQALHRSRKLHQQYRLARQRIIQFQARCRAYLVRKAFRHRLWAV
  LTVQAYARGMIARRLHQRLRAEYLWRLEAEKMRLAEEEKLRKEMSAKKAKEEAERKHQER
  LAQLAREDAERELKEKEAARRKKELLEQMERARHEPVNHSDMVDKMFGFLGTSGGLPGQE
  GQAPSGFEDLERGRREMVEEDLDAALPLPDEDEEDLSEYKFAKFAATYFQGTTTHSYTRR
  PLKQPLLYHDDEGDQLAALAVWITILRFMGDLPEPKYHTAMSDGSEKIPVMTKIYETLGK
  KTYKRELQALQGEGEAQLPEGQKKSSVRHKLVHLTLKKKSKLTEEVTKRLHDGESTVQGN
  SMLEDRPTSNLEKLHFIIGNGILRPALRDEIYCQISKQLTHNPSKSSYARGWILVSLCVG
  CFAPSEKFVKYLRNFIHGGPPGYAPYCEERLRRTFVNGTRTQPPSWLELQATKSKKPIML
  PVTFMDGTTKTLLTDSATTAKELCNALADKISLKDRFGFSLYIALFDKVSSLGSGSDHVM
  DAISQCEQYAKEQGAQERNAPWRLFFRKEVFTPWHSPSEDNVATNLIYQQVVRGVKFGEY
  RCEKEDDLAELASQQYFVDYGSEMILERLLNLVPTYIPDREITPLKTLEKWAQLAIAAHK
  KGIYAQRRTDAQKVKEDVVSYARFKWPLLFSRFYEAYKFSGPSLPKNDVIVAVNWTGVYF
  VDEQEQVLLELSFPEIMAVSSSRECRVWLSLGCSDLGCAAPHSGWAGLTPAGPCSPCWSC
  RGAKTTAPSFTLATIKGDEYTFTSSNAEDIRDLVVTFLEGLRKRSKYVVALQDNPNPAGE
  ESGFLSFAKGDLIILDHDTGEQVMNSGWANGINERTKQRGDFPTDSVYVMPTVTMPPREI
  VALVTMTPDQRQDVVRLLQLRTAEPEVRAKPYTLEEFSYDYFRPPPKHTLSRVMVSKARG
  KDRLWSHTREPLKQALLKKLLGSEELSQEACLAFIAVLKYMGDYPSKRTRSVNELTDQIF
  EGPLKAEPLKDEAYVQILKQLTDNHIRYSEERGWELLWLCTGLFPPSNILLPHVQRFLQS
  RKHCPLAIDCLQRLQKALRNGSRKYPPHLVEVEAIQHKTTQIFHKVYFPDDTDEAFEVES
  STKAKDFCQNIATRLLLKSSEGFSLFVKIADKVLSVPENDFFFDFVRHLTDWIKKARPIK
  DGIVPSLTYQVFFMKKLWTTTVPGKDPMADSIFHYYQELPKYLRGYHKCTREEVLQLGAL
  IYRVKFEEDKSYFPSIPKLLRELVPQDLIRQVSPDDWKRSIVAYFNKHAGKSKEEAKLAF
  LKLIFKWPTFGSAFFEVKQTTEPNFPEILLIAINKYGVSLIDPKTKDILTTHPFTKISNW
  SSGNTYFHITIGNLVRGSKLLCETSLGYKMDDLLTSYISQMLTAMSKQRGSRSGK
• Function: Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. Their highly divergent tails bind to membranous compartments, which are then moved relative to actin filaments. In the retina, plays an important role in the renewal of the outer photoreceptor disks. Plays an important role in the distribution and migration of retinal pigment epithelial (RPE) melanosomes and phagosomes, and in the regulation of opsin transport in retinal photoreceptors. In the inner ear, plays an important role in differentiation, morphogenesis and organization of cochlear hair cell bundles. Involved in hair-cell vesicle trafficking of aminoglycosides, which are known to induce ototoxicity. Motor protein that is a part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells. Required for normal hearing.
• Tissue Specificity: Expressed in the pigment epithelium and the photoreceptor cells of the retina. Also found in kidney, liver, testis, cochlea, lymphocytes. Not expressed in brain.
• KEGG Pathway: Motor proteins (hsa04814)
• Reactome Pathway:
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)
  Sensory processing of sound by outer hair cells of the cochlea (R-HSA-9662361)
  The canonical retinoid cycle in rods (twilight vision) (R-HSA-2453902)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant nonsyndromic hearing loss 12	DISPBW4Z	Definitive	Genetic Variation	[1]
Autosomal recessive nonsyndromic hearing loss 2	DIS1P51S	Definitive	Autosomal recessive	[2]
Metastatic malignant neoplasm	DIS86UK6	Definitive	Biomarker	[3]
Nonsyndromic genetic hearing loss	DISZX61P	Definitive	Autosomal dominant	[4]
Usher syndrome type 1	DISR29E4	Definitive	Autosomal recessive	[4]
Usher syndrome type 1B	DISWTUHR	Definitive	Autosomal recessive	[5]
Auditory neuropathy	DISM6GAU	Strong	Biomarker	[6]
Autosomal dominant nonsyndromic hearing loss 11	DISGBZRR	Strong	Autosomal dominant	[7]
Autosomal dominant nonsyndromic hearing loss 13	DISFLETQ	Strong	Genetic Variation	[6]
Autosomal dominant nonsyndromic hearing loss 9	DISD5HDW	Strong	Biomarker	[6]
Bardet biedl syndrome	DISTBNZW	Strong	Genetic Variation	[8]
Blindness	DISTIM10	Strong	Genetic Variation	[9]
Deafness	DISKCLH4	Strong	Genetic Variation	[10]
Lung cancer	DISCM4YA	Strong	Biomarker	[11]
Lung carcinoma	DISTR26C	Strong	Biomarker	[11]
Melanoma	DIS1RRCY	Strong	Biomarker	[3]
Usher syndrome	DIS9YIS7	Strong	Genetic Variation	[12]
Usher syndrome type 2D	DISHEVUD	Strong	GermlineCausalMutation	[13]
Usher syndrome type 3	DISRAL84	Strong	Biomarker	[14]
Age-related macular degeneration	DIS0XS2C	moderate	Altered Expression	[15]
Ear malformation	DISVJGPS	moderate	Genetic Variation	[16]
Retinopathy	DISB4B0F	moderate	Genetic Variation	[17]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[18]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[18]
Usher syndrome type 2	DIS3LO3C	Supportive	Autosomal recessive	[13]
Leber congenital amaurosis	DISMGH8F	Limited	Genetic Variation	[19]
Retinitis pigmentosa	DISCGPY8	Limited	CausalMutation	[20]
Severe early-childhood-onset retinal dystrophy	DISFDRFO	Limited	Genetic Variation	[21]

5 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 Unconventional myosin-VIIa (MYO7A).	[22]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Unconventional myosin-VIIa (MYO7A).	[24]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Unconventional myosin-VIIa (MYO7A).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Unconventional myosin-VIIa (MYO7A).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Unconventional myosin-VIIa (MYO7A).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Unconventional myosin-VIIa (MYO7A).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Unconventional myosin-VIIa (MYO7A).	[27]

References

• [1] A gene for autosomal dominant nonsyndromic hearing loss (DFNA12) maps to chromosome 11q22-24.Am J Hum Genet. 1997 May;60(5):1168-73.
• [2] The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene. Nat Genet. 1997 Jun;16(2):191-3. doi: 10.1038/ng0697-191.
• [3] Unconventional myosin VIIA promotes melanoma progression.J Cell Sci. 2018 Feb 22;131(4):jcs209924. doi: 10.1242/jcs.209924.
• [4] 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.
• [5] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [6] Hereditary deafness and phenotyping in humans.Br Med Bull. 2002;63:73-94. doi: 10.1093/bmb/63.1.73.
• [7] Autosomal dominant non-syndromic deafness caused by a mutation in the myosin VIIA gene. Nat Genet. 1997 Nov;17(3):268-9. doi: 10.1038/ng1197-268.
• [8] The cloning and developmental expression of unconventional myosin IXA (MYO9A) a gene in the Bardet-Biedl syndrome (BBS4) region at chromosome 15q22-q23.Genomics. 1999 Jul 15;59(2):150-60. doi: 10.1006/geno.1999.5867.
• [9] Detecting novel mutations and combined Klinefelter syndrome in Usher syndrome cases.Acta Otolaryngol. 2019 Jun;139(6):479-486. doi: 10.1080/00016489.2019.1603397. Epub 2019 Apr 29.
• [10] Genetics of Usher Syndrome: New Insights From a Meta-analysis.Otol Neurotol. 2019 Jan;40(1):121-129. doi: 10.1097/MAO.0000000000002054.
• [11] Integrative system genetic analysis reveals mRNA-lncRNA network associated with mouse spontaneous lung cancer susceptibility.Oncotarget. 2019 Jan 8;10(3):339-351. doi: 10.18632/oncotarget.26554. eCollection 2019 Jan 8.
• [12] Identification of four novel mutations in MYO7A gene and their association with nonsyndromic deafness and Usher Syndrome 1B.Int J Pediatr Otorhinolaryngol. 2019 May;120:166-172. doi: 10.1016/j.ijporl.2019.02.021. Epub 2019 Feb 11.
• [13] Novel and recurrent MYO7A mutations in Usher syndrome type 1 and type 2. PLoS One. 2014 May 15;9(5):e97808. doi: 10.1371/journal.pone.0097808. eCollection 2014.
• [14] Identification of a rat model for usher syndrome type 1B by N-ethyl-N-nitrosourea mutagenesis-driven forward genetics.Genetics. 2005 Aug;170(4):1887-96. doi: 10.1534/genetics.105.044222. Epub 2005 Jun 18.
• [15] Mitochondrial DNA variants mediate energy production and expression levels for CFH, C3 and EFEMP1 genes: implications for age-related macular degeneration.PLoS One. 2013;8(1):e54339. doi: 10.1371/journal.pone.0054339. Epub 2013 Jan 24.
• [16] Myosin VIIA defects, which underlie the Usher 1B syndrome in humans, lead to deafness in Drosophila.Curr Biol. 2005 May 10;15(9):862-8. doi: 10.1016/j.cub.2005.03.050.
• [17] Reinforcement of a minor alternative splicing event in MYO7A due to a missense mutation results in a mild form of retinopathy and deafness.Mol Vis. 2010 Sep 30;16:1898-906.
• [18] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [19] Assessment of different virus-mediated approaches for retinal gene therapy of Usher 1B.Adv Exp Med Biol. 2014;801:725-31. doi: 10.1007/978-1-4614-3209-8_91.
• [20] Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.Sci Rep. 2019 Feb 4;9(1):1219. doi: 10.1038/s41598-018-38007-2.
• [21] Efficient gene delivery to the cone-enriched pig retina by dual AAV vectors.Gene Ther. 2014 Apr;21(4):450-6. doi: 10.1038/gt.2014.8. Epub 2014 Feb 27.
• [22] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [23] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [24] 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.
• [25] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [26] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [27] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [28] 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.