词条 | TMC1 |
释义 |
FunctionThis gene is considered a member of a gene family predicted to encode transmembrane proteins. Until recently, the specific function of this gene was relatively unknown; it was only known to be required for normal function of cochlear hair cells.[3] However, new research suggests that TMC1 interacts with Tip link proteins protocadherin 15 and cadherin 23 indicating that TMC1, along with TMC2, are necessary proteins for hair cell mechanotransduction.[6] Specifically, TMC1 and TMC2 may be two pore-forming subunits of the channel that responds to tip link deflection in hair cells.[7] Due to its implication in cochlear hair cell function and its interaction with hair cell tip links, TMC1 is being mutated and manipulated in order to better understand the receptor while at the same time producing a molecular model for deafness. While deafness can arise at any stage of auditory processing, DFNA36 (a type of progressive hearing loss) and DFNB7/B11 (congenital hearing loss) have been specifically shown to arise from TMC1 mutations. DFNA36 results from a dominant missense mutation and DFNB7/B11 results from a recessive mutation.[1] Both have been modeled in mice, known as the Beethoven model and the dn model respectively.[2] The TMC1 gene is located on chromosome 9q31-q21, and the dominant mutation associated with DFNA36 occurs at amino acid 572[8] which suggests the importance of this amino acid in the overall function of TMC1. Now that TMC1 has been shown to interact with the tip link proteins PCDH15 and CDH23,[6] the next question may be whether or not amino acid 572 is necessary for TMC1 tip link interactions. Researchers reported in 2015 that genetically deaf mice treated with TMC1 gene therapy recovered some of their hearing.[9][10] Clinical significanceMutations in this gene have been associated with progressive postlingual hearing loss, {{SWL|type=mutations_associated_to|target=Non-syndromic deafness|label=non syndromic deafness}}[11] and profound prelingual deafness.[3] TMC1 mutations are not associated with other symptoms or abnormalities, which is known as Nonsyndromic hearing loss and indicates that TMC1 functions mainly in auditory sensation.[12] Additionally, recessive mutations of the gene result in both a loss of TMC1 function as well as profound deafness[8] indicating TMC1 function is necessary for the processing of auditory signals. References1. ^1 2 3 {{cite journal | vauthors = Kurima K, Peters LM, Yang Y, Riazuddin S, Ahmed ZM, Naz S, Arnaud D, Drury S, Mo J, Makishima T, Ghosh M, Menon PS, Deshmukh D, Oddoux C, Ostrer H, Khan S, Riazuddin S, Deininger PL, Hampton LL, Sullivan SL, Battey JF, Keats BJ, Wilcox ER, Friedman TB, Griffith AJ | title = Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function | journal = Nat Genet | volume = 30 | issue = 3 | pages = 277–84 | date = Mar 2002 | pmid = 11850618 | pmc = | doi = 10.1038/ng842 }} 2. ^1 {{cite journal | vauthors = Vreugde S, Erven A, Kros CJ, Marcotti W, Fuchs H, Kurima K, Wilcox ER, Friedman TB, Griffith AJ, Balling R, Hrabé De Angelis M, Avraham KB, Steel KP | title = Beethoven, a mouse model for dominant, progressive hearing loss DFNA36 | journal = Nat Genet | volume = 30 | issue = 3 | pages = 257–8 | year = 2002 | pmid = 11850623 | pmc = | doi = 10.1038/ng848 }} 3. ^1 2 {{cite web | title = Entrez Gene: TMC1 transmembrane channel-like 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=117531| accessdate = }} 4. ^{{cite journal | vauthors = Vriens J, Nilius B, Voets T | title = Peripheral thermosensation in mammals | journal = Nature Reviews Neuroscience | volume = 15 | issue = 9 | pages = 573–89 | year = 2014 | pmid = 25053448 | doi = 10.1038/nrn3784 }} 5. ^{{cite journal | vauthors = Kawashima Y, Géléoc GS, Kurima K, Labay V, Lelli A, Asai Y, Makishima T, Wu DK, Della Santina CC, Holt JR, Griffith AJ | title = Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes | journal = J. Clin. Invest. | volume = 121 | issue = 12 | pages = 4796–809 | year = 2011 | pmid = 22105175 | pmc = 3223072 | doi = 10.1172/JCI60405 }} 6. ^1 {{cite journal | vauthors = Maeda R, Kindt KS, Mo W, Morgan CP, Erickson T, Zhao H, Clemens-Grisham R, Barr-Gillespie PG, Nicolson T | title = Tip-link protein protocadherin 15 interacts with transmembrane channel-like proteins TMC1 and TMC2 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 111 | issue = 35 | pages = 12907–12 | year = 2014 | pmid = 25114259 | doi = 10.1073/pnas.1402152111 | pmc=4156717}} 7. ^{{cite journal | vauthors = Pan B, Géléoc GS, Asai Y, Horwitz GC, Kurima K, Ishikawa K, Kawashima Y, Griffith AJ, Holt JR | title = TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear | journal = Neuron | volume = 79 | issue = 3 | pages = 504–15 | year = 2013 | pmid = 23871232 | pmc = 3827726 | doi = 10.1016/j.neuron.2013.06.019 }} 8. ^1 {{cite journal | vauthors = Kitajiri S, Makishima T, Friedman TB, Griffith AJ | title = A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype-phenotype correlation for amino acid-572 of TMC1 | journal = Clin. Genet. | volume = 71 | issue = 2 | pages = 148–52 | year = 2007 | pmid = 17250663 | doi = 10.1111/j.1399-0004.2007.00739.x }} 9. ^{{cite news |last= Gallacher|first= James |date= 9 July 2015|title= Deafness could be treated by virus, say scientists|url= https://www.bbc.co.uk/news/health-33442820|publisher= BBC|location= UK|access-date= 9 July 2015}} 10. ^{{cite journal |last= Askew|first= Charles|date= 8 July 2015|title= Tmc gene therapy restores auditory function in deaf mice|url= |journal= Science Translational Medicine|publisher= American Association for the Advancement of Science|volume= 7|issue= 295|pages= 295ra108|doi= 10.1126/scitranslmed.aab1996|display-authors=etal|pmid=26157030}} 11. ^{{cite journal | vauthors = Riahi Z, Bonnet C, Zainine R, Louha M, Bouyacoub Y, Laroussi N, Chargui M, Kefi R, Jonard L, Dorboz I, Hardelin JP, Salah SB, Levilliers J, Weil D, McElreavey K, Boespflug OT, Besbes G, Abdelhak S, Petit C | title = Whole Exome Sequencing Identifies New Causative Mutations in Tunisian Families with Non-Syndromic Deafness | journal = PLoS ONE | volume = 9 | issue = 6 | pages = e99797 | year = 2014 | pmid = 24926664 | doi = 10.1371/journal.pone.0099797 | pmc=4057390}} 12. ^{{cite journal | vauthors = Duman D, Tekin M | title = Autosomal recessive nonsyndromic deafness genes: a review | journal = Front Biosci | volume = 17 | issue = | pages = 2213–36 | year = 2012 | pmid = 22652773 | pmc = 3683827 | doi = 10.2741/4046}} Further reading{{refbegin|35em}}
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