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| Subject | Predicate | Object |
|---|---|---|
| http://purl.uniprot.org/citations/33824189 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/33824189 | http://www.w3.org/2000/01/rdf-schema#comment | "Transmembrane channel-like protein isoform 1 (TMC1) is a major component of the mechano-electrical transducer (MET) channel in cochlear hair cells and is subject to numerous mutations causing deafness. We report a new dominant human deafness mutation, TMC1 p.T422K, and have characterized the homologous mouse mutant, Tmc1 p.T416K, which caused deafness and outer hair cell (OHC) loss by the fourth postnatal week. MET channels showed decreased Ca2+ permeability and resting open probability, but no change in single-channel conductance or expression. Three adjacent deafness mutations are TMC1 p.L416R, p.G417R, and p.M418K, the last homologous to the mouse Beethoven that exhibits similar channel effects. All substitute a positive for a neutral residue, which could produce charge screening in the channel pore or influence binding of an accessory subunit. Channel properties were compared in mice of both sexes between dominant (Tmc1 p.T416K, Tmc1 p.D569N) and recessive (Tmc1 p.W554L, Tmc1 p.D528N) mutations of residues near the putative pore of the channel. Tmc1 p.W554L and p.D569N exhibit reduced maximum current with no effect on single-channel conductance, implying a smaller number of channels transported to the stereociliary tips; this may stem from impaired TMC1 binding to LHFPL5. Tmc1 p.D528N, located in the pore's narrowest region, uniquely caused large reductions in MET channel conductance and block by dihydrostreptomycin (DHS). For Tmc1 p.T416K and Tmc1 p.D528N, transduction loss occurred between P15 and P20. We propose two mechanisms linking channel mutations and deafness: decreased Ca2+ permeability, common to all mutants, and decreased resting open probability in low Ca2+, confined to dominant mutations.SIGNIFICANCE STATEMENT Transmembrane channel-like protein isoform 1 (TMC1) is thought to be a major component of the mechanotransducer channel in auditory hair cells, but the protein organization and channel structure are still uncertain. We made four mouse lines harboring Tmc1 point mutations that alter channel properties, causing hair cell degeneration and deafness. These include a mouse homolog of a new human deafness mutation pT416K that decreased channel Ca2+ permeability by introducing a positively-charged amino acid in the putative pore. All mutations are consistent with the channel structure predicted from modeling, but only one, p.D528N near the external face of the pore, substantially reduced channel conductance and Ca2+ permeability and virtually abolished block by dihydrostreptomycin (DHS), strongly endorsing its siting within the pore."xsd:string |
| http://purl.uniprot.org/citations/33824189 | http://purl.org/dc/terms/identifier | "doi:10.1523/jneurosci.2537-20.2021"xsd:string |
| http://purl.uniprot.org/citations/33824189 | http://purl.uniprot.org/core/author | "Ballesteros A."xsd:string |
| http://purl.uniprot.org/citations/33824189 | http://purl.uniprot.org/core/author | "Barlow A.J."xsd:string |
| http://purl.uniprot.org/citations/33824189 | http://purl.uniprot.org/core/author | "Fettiplace R."xsd:string |
| http://purl.uniprot.org/citations/33824189 | http://purl.uniprot.org/core/author | "Amr S.S."xsd:string |
| http://purl.uniprot.org/citations/33824189 | http://purl.uniprot.org/core/author | "Schimmenti L.A."xsd:string |
| http://purl.uniprot.org/citations/33824189 | http://purl.uniprot.org/core/author | "Beurg M."xsd:string |
| http://purl.uniprot.org/citations/33824189 | http://purl.uniprot.org/core/author | "Koleilat A."xsd:string |
| http://purl.uniprot.org/citations/33824189 | http://purl.uniprot.org/core/author | "Oza A."xsd:string |
| http://purl.uniprot.org/citations/33824189 | http://purl.uniprot.org/core/date | "2021"xsd:gYear |
| http://purl.uniprot.org/citations/33824189 | http://purl.uniprot.org/core/name | "J Neurosci"xsd:string |
| http://purl.uniprot.org/citations/33824189 | http://purl.uniprot.org/core/pages | "4378-4391"xsd:string |
| http://purl.uniprot.org/citations/33824189 | http://purl.uniprot.org/core/title | "New Tmc1 Deafness Mutations Impact Mechanotransduction in Auditory Hair Cells."xsd:string |
| http://purl.uniprot.org/citations/33824189 | http://purl.uniprot.org/core/volume | "41"xsd:string |
| http://purl.uniprot.org/citations/33824189 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/33824189 |
| http://purl.uniprot.org/citations/33824189 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/33824189 |
| http://purl.uniprot.org/uniprot/#_A4FU59-mappedCitation-33824189 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/33824189 |
| http://purl.uniprot.org/uniprot/#_A5D8Y1-mappedCitation-33824189 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/33824189 |
| http://purl.uniprot.org/uniprot/#_A0A494BB39-mappedCitation-33824189 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/33824189 |
| http://purl.uniprot.org/uniprot/#_A0A6S6MPY2-mappedCitation-33824189 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/33824189 |
| http://purl.uniprot.org/uniprot/#_A4FUA6-mappedCitation-33824189 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/33824189 |
| http://purl.uniprot.org/uniprot/#_Q3MI88-mappedCitation-33824189 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/33824189 |
| http://purl.uniprot.org/uniprot/#_Q8CCC1-mappedCitation-33824189 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/33824189 |