Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHYH8MU)

• DOT Name: Transmembrane channel-like protein 1 (TMC1)
• Synonyms: Transmembrane cochlear-expressed protein 1
• Gene Name: TMC1
• Related Disease:
  Autosomal recessive nonsyndromic hearing loss 7
  Nonsyndromic genetic hearing loss
  Autosomal dominant nonsyndromic hearing loss 36
  Ear disease
  Sensorineural hearing loss disorder
  Autosomal dominant nonsyndromic hearing loss
  Hearing loss, autosomal recessive
  Nasopharyngeal carcinoma
  Neoplasm of esophagus
• UniProt ID: TMC1_HUMAN
• Pfam ID: PF07810
• Sequence:
  MSPKKVQIKVEEKEDETEESSSEEEEEVEDKLPRRESLRPKRKRTRDVINEDDPEPEPED
  EETRKAREKERRRRLKRGAEEEEIDEEELERLKAELDEKRQIIATVKCKPWKMEKKIEVL
  KEAKKFVSENEGALGKGKGKRWFAFKMMMAKKWAKFLRDFENFKAACVPWENKIKAIESQ
  FGSSVASYFLFLRWMYGVNMVLFILTFSLIMLPEYLWGLPYGSLPRKTVPRAEEASAANF
  GVLYDFNGLAQYSVLFYGYYDNKRTIGWMNFRLPLSYFLVGIMCIGYSFLVVLKAMTKNI
  GDDGGGDDNTFNFSWKVFTSWDYLIGNPETADNKFNSITMNFKEAITEEKAAQVEENVHL
  IRFLRFLANFFVFLTLGGSGYLIFWAVKRSQEFAQQDPDTLGWWEKNEMNMVMSLLGMFC
  PTLFDLFAELEDYHPLIALKWLLGRIFALLLGNLYVFILALMDEINNKIEEEKLVKANIT
  LWEANMIKAYNASFSENSTGPPFFVHPADVPRGPCWETMVGQEFVRLTVSDVLTTYVTIL
  IGDFLRACFVRFCNYCWCWDLEYGYPSYTEFDISGNVLALIFNQGMIWMGSFFAPSLPGI
  NILRLHTSMYFQCWAVMCCNVPEARVFKASRSNNFYLGMLLLILFLSTMPVLYMIVSLPP
  SFDCGPFSGKNRMFEVIGETLEHDFPSWMAKILRQLSNPGLVIAVILVMVLAIYYLNATA
  KGQKAANLDLKKKMKMQALENKMRNKKMAAARAAAAAGRQ
• Function: Probable ion channel required for the normal function of cochlear hair cells.
• Tissue Specificity: Detected in fetal cochlea, and at low levels in placenta and testis.
• Reactome Pathway:
  Sensory processing of sound by outer hair cells of the cochlea (R-HSA-9662361)
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive nonsyndromic hearing loss 7	DISJIHMA	Definitive	Autosomal recessive	[1]
Nonsyndromic genetic hearing loss	DISZX61P	Definitive	Autosomal dominant	[1]
Autosomal dominant nonsyndromic hearing loss 36	DIS33XI0	Strong	Autosomal dominant	[2]
Ear disease	DISCL1WZ	Strong	Biomarker	[3]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[4]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[5]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[5]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[6]
Neoplasm of esophagus	DISOLKAQ	Limited	Genetic Variation	[7]

2 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 Transmembrane channel-like protein 1 (TMC1).	[8]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Transmembrane channel-like protein 1 (TMC1).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Transmembrane channel-like protein 1 (TMC1).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Transmembrane channel-like protein 1 (TMC1).	[11]

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] Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nat Genet. 2002 Mar;30(3):277-84. doi: 10.1038/ng842. Epub 2002 Feb 19.
• [3] Publisher Correction: Improved TMC1 gene therapy restores hearing and balance in mice with genetic inner ear disorders.Nat Commun. 2019 Feb 8;10(1):734. doi: 10.1038/s41467-019-08716-x.
• [4] Identification of four TMC1 variations in different Chinese families with hereditary hearing loss.Mol Genet Genomic Med. 2018 Apr 14;6(4):504-13. doi: 10.1002/mgg3.394. Online ahead of print.
• [5] 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.
• [6] Epstein-Barr virus LMP1 modulates the malignant potential of gastric carcinoma cells involving apoptosis.Am J Pathol. 1998 Jan;152(1):63-74.
• [7] Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions.Nat Genet. 2012 Oct;44(10):1090-7. doi: 10.1038/ng.2411. Epub 2012 Sep 9.
• [8] 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.
• [9] 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.
• [10] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [11] Transcriptomic?pathway?and?benchmark dose analysis of Bisphenol A, Bisphenol S, Bisphenol F, and 3,3',5,5'-Tetrabromobisphenol A in H9 human embryonic stem cells. Toxicol In Vitro. 2021 Apr;72:105097. doi: 10.1016/j.tiv.2021.105097. Epub 2021 Jan 18.