Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXQMJY8)

• DOT Name: Otoferlin (OTOF)
• Synonyms: Fer-1-like protein 2
• Gene Name: OTOF
• Related Disease:
  Autosomal recessive nonsyndromic hearing loss 9
  Alzheimer disease
  Alzheimer disease 3
  Autosomal recessive nonsyndromic hearing loss 4
  Deafness
  Hypothyroidism
  Sensorineural hearing loss disorder
  Usher syndrome
  Pendred syndrome
  Hearing loss, autosomal recessive
  Auditory neuropathy
• UniProt ID: OTOF_HUMAN
• Pfam ID: PF00168 ; PF08150 ; PF08151 ; PF16165
• Sequence:
  MALLIHLKTVSELRGRGDRIAKVTFRGQSFYSRVLENCEDVADFDETFRWPVASSIDRNE
  MLEIQVFNYSKVFSNKLIGTFRMVLQKVVEESHVEVTDTLIDDNNAIIKTSLCVEVRYQA
  TDGTVGSWDDGDFLGDESLQEEEKDSQETDGLLPGSRPSSRPPGEKSFRRAGRSVFSAMK
  LGKNRSHKEEPQRPDEPAVLEMEDLDHLAIRLGDGLDPDSVSLASVTALTTNVSNKRSKP
  DIKMEPSAGRPMDYQVSITVIEARQLVGLNMDPVVCVEVGDDKKYTSMKESTNCPYYNEY
  FVFDFHVSPDVMFDKIIKISVIHSKNLLRSGTLVGSFKMDVGTVYSQPEHQFHHKWAILS
  DPDDISSGLKGYVKCDVAVVGKGDNIKTPHKANETDEDDIEGNLLLPEGVPPERQWARFY
  VKIYRAEGLPRMNTSLMANVKKAFIGENKDLVDPYVQVFFAGQKGKTSVQKSSYEPLWNE
  QVVFTDLFPPLCKRMKVQIRDSDKVNDVAIGTHFIDLRKISNDGDKGFLPTLGPAWVNMY
  GSTRNYTLLDEHQDLNEGLGEGVSFRARLLLGLAVEIVDTSNPELTSSTEVQVEQATPIS
  ESCAGKMEEFFLFGAFLEASMIDRRNGDKPITFEVTIGNYGNEVDGLSRPQRPRPRKEPG
  DEEEVDLIQNASDDEAGDAGDLASVSSTPPMRPQVTDRNYFHLPYLERKPCIYIKSWWPD
  QRRRLYNANIMDHIADKLEEGLNDIQEMIKTEKSYPERRLRGVLEELSCGCCRFLSLADK
  DQGHSSRTRLDRERLKSCMRELENMGQQARMLRAQVKRHTVRDKLRLCQNFLQKLRFLAD
  EPQHSIPDIFIWMMSNNKRVAYARVPSKDLLFSIVEEETGKDCAKVKTLFLKLPGKRGFG
  SAGWTVQAKVELYLWLGLSKQRKEFLCGLPCGFQEVKAAQGLGLHAFPPVSLVYTKKQAF
  QLRAHMYQARSLFAADSSGLSDPFARVFFINQSQCTEVLNETLCPTWDQMLVFDNLELYG
  EAHELRDDPPIIVIEIYDQDSMGKADFMGRTFAKPLVKMADEAYCPPRFPPQLEYYQIYR
  GNATAGDLLAAFELLQIGPAGKADLPPINGPVDVDRGPIMPVPMGIRPVLSKYRVEVLFW
  GLRDLKRVNLAQVDRPRVDIECAGKGVQSSLIHNYKKNPNFNTLVKWFEVDLPENELLHP
  PLNIRVVDCRAFGRYTLVGSHAVSSLRRFIYRPPDRSAPSWNTTVRLLRRCRVLCNGGSS
  SHSTGEVVVTMEPEVPIKKLETMVKLDATSEAVVKVDVAEEEKEKKKKKKGTAEEPEEEE
  PDESMLDWWSKYFASIDTMKEQLRQQEPSGIDLEEKEEVDNTEGLKGSMKGKEKARAAKE
  EKKKKTQSSGSGQGSEAPEKKKPKIDELKVYPKELESEFDNFEDWLHTFNLLRGKTGDDE
  DGSTEEERIVGRFKGSLCVYKVPLPEDVSREAGYDSTYGMFQGIPSNDPINVLVRVYVVR
  ATDLHPADINGKADPYIAIRLGKTDIRDKENYISKQLNPVFGKSFDIEASFPMESMLTVA
  VYDWDLVGTDDLIGETKIDLENRFYSKHRATCGIAQTYSTHGYNIWRDPMKPSQILTRLC
  KDGKVDGPHFGPPGRVKVANRVFTGPSEIEDENGQRKPTDEHVALLALRHWEDIPRAGCR
  LVPEHVETRPLLNPDKPGIEQGRLELWVDMFPMDMPAPGTPLDISPRKPKKYELRVIIWN
  TDEVVLEDDDFFTGEKSSDIFVRGWLKGQQEDKQDTDVHYHSLTGEGNFNWRYLFPFDYL
  AAEEKIVISKKESMFSWDETEYKIPARLTLQIWDADHFSADDFLGAIELDLNRFPRGAKT
  AKQCTMEMATGEVDVPLVSIFKQKRVKGWWPLLARNENDEFELTGKVEAELHLLTAEEAE
  KNPVGLARNEPDPLEKPNRPDTSFIWFLNPLKSARYFLWHTYRWLLLKLLLLLLLLLLLA
  LFLYSVPGYLVKKILGA
• Function: Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion and in the control of neurotransmitter release at these output synapses. Interacts in a calcium-dependent manner to the presynaptic SNARE proteins at ribbon synapses of cochlear inner hair cells (IHCs) to trigger exocytosis of neurotransmitter. Also essential to synaptic exocytosis in immature outer hair cells (OHCs). May also play a role within the recycling of endosomes.
• Tissue Specificity: Isoform 1 and isoform 3 are found in adult brain. Isoform 2 is expressed in the fetus and in adult brain, heart, placenta, skeletal muscle and kidney.
• Reactome Pathway:
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)
  Insertion of tail-anchored proteins into the endoplasmic reticulum membrane (R-HSA-9609523)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive nonsyndromic hearing loss 9	DISUKXHK	Definitive	Autosomal recessive	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Alzheimer disease 3	DISVT69G	Strong	Genetic Variation	[3]
Autosomal recessive nonsyndromic hearing loss 4	DISCJIDF	Strong	Biomarker	[4]
Deafness	DISKCLH4	Strong	Biomarker	[5]
Hypothyroidism	DISR0H6D	Strong	Biomarker	[6]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[7]
Usher syndrome	DIS9YIS7	Strong	Biomarker	[8]
Pendred syndrome	DISZ1MU8	moderate	Genetic Variation	[9]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[10]
Auditory neuropathy	DISM6GAU	Limited	Biomarker	[11]

4 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Otoferlin (OTOF).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Otoferlin (OTOF).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Otoferlin (OTOF).	[12]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Otoferlin (OTOF).	[13]

3 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 Otoferlin (OTOF).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Otoferlin (OTOF).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Otoferlin (OTOF).	[16]

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] Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.
• [3] Identification of a novel splice site variant of OTOF in the Korean nonsyndromic hearing loss population with low prevalence of the OTOF mutations.Int J Pediatr Otorhinolaryngol. 2014 Jul;78(7):1030-5. doi: 10.1016/j.ijporl.2014.03.033. Epub 2014 Apr 24.
• [4] Hereditary deafness and phenotyping in humans.Br Med Bull. 2002;63:73-94. doi: 10.1093/bmb/63.1.73.
• [5] Mutations in OTOF, CLDN14 & SLC26A4 genes as major causes of hearing impairment in Dhadkai village, Jammu & Kashmir, India.Indian J Med Res. 2017 Oct;146(4):489-497. doi: 10.4103/ijmr.IJMR_635_15.
• [6] Thyroid hormone deficiency affects postnatal spiking activity and expression of Ca2+ and K+ channels in rodent inner hair cells.J Neurosci. 2007 Mar 21;27(12):3174-86. doi: 10.1523/JNEUROSCI.3965-06.2007.
• [7] OTOF mutation analysis with massively parallel DNA sequencing in 2,265 Japanese sensorineural hearing loss patients.PLoS One. 2019 May 16;14(5):e0215932. doi: 10.1371/journal.pone.0215932. eCollection 2019.
• [8] Mouse models for human hereditary deafness.Curr Top Dev Biol. 2008;84:385-429. doi: 10.1016/S0070-2153(08)00608-X.
• [9] Deafness heterogeneity in a Druze isolate from the Middle East: novel OTOF and PDS mutations, low prevalence of GJB2 35delG mutation and indication for a new DFNB locus.Eur J Hum Genet. 2000 Jun;8(6):437-42. doi: 10.1038/sj.ejhg.5200489.
• [10] 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.
• [11] Mutational and phenotypic spectrum of OTOF-related auditory neuropathy in Koreans: eliciting reciprocal interaction between bench and clinics.J Transl Med. 2018 Nov 27;16(1):330. doi: 10.1186/s12967-018-1708-z.
• [12] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [13] Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells. J Appl Toxicol. 2007 Jan-Feb;27(1):67-77. doi: 10.1002/jat.1200.
• [14] 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.
• [15] 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.
• [16] 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.