A
            <i>Tmc1</i>
            mutation reduces calcium permeability and expression of mechanoelectrical transduction channels in cochlear hair cells

Beurg, Maryline; Barlow, Amanda; Furness, David N.; Fettiplace, Robert

doi:10.1073/pnas.1908058116

Cited by 52 publications

(67 citation statements)

References 42 publications

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“…The maximum MET current in OHCs developed over the first week, becoming maximal at P4 at the base of the cochlea and P6 at the apex. Unlike Tmc1 p.D569N (Beurg et al, 2019), tonotopy was preserved and the maximum current though reduced was still larger at the base than at the apex. In contrast, there was no effect on single channel current (Fig.…”

Section: Figure 8 Near Herementioning

confidence: 86%

“…Another mutation in the latter category besides the Tmc1 p.W554L/W554L is at a nearby intracellular site Tmc1 p.D569N/D569N (Beurg et al, 2019) and had 46 ± 18 (N= 5) channels.…”

Section: Discussionmentioning

confidence: 99%

“…Mouse mutants. Tmc1 p.D569N and Tmc1 p.W554L mutant mice were made by Applied StemCell Inc (Milpitas, CA) (Beurg et al, 2019) and Tmc1 p.D528N and Tmc1 p.T416K mice were made by Horizon Sage Labs Inc (Saint Louis, MO), all using CRISPR/Cas9 technology.…”

Section: Methodsmentioning

confidence: 99%

“…To document hair cell survival in mutants, isolated cochleas were fixed in 4% paraformaldehyde for 1 h at room temperature, processed (Beurg et al, 2019) and immunolabeled with rabbit monoclonal anti-calbindinD28k (Swant, Bellinoza Switzerland, 1:500, 2 h), and Alexa568…”

Section: Hair Cell Survivalmentioning

confidence: 99%

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New Tmc1 Deafness Mutations Impact Mechanotransduction in Auditory Hair Cells

et al. 2021

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Transmembrane channel-like protein isoform 1 (TMC1) is a major component of the mechanoelectrical 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 SignificanceTransmembrane 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 Ca 2+ permeability by introducing a positively-charged amino acid in the putative pore. All mutations are largely 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 Ca 2+ permeability and virtually abolished block by dihydrostreptomycin, strongly endorsing its siting within the pore.

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Section: Figure 8 Near Herementioning

confidence: 86%

“…Another mutation in the latter category besides the Tmc1 p.W554L/W554L is at a nearby intracellular site Tmc1 p.D569N/D569N (Beurg et al, 2019) and had 46 ± 18 (N= 5) channels.…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Hair Cell Survivalmentioning

confidence: 99%

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New Tmc1 Deafness Mutations Impact Mechanotransduction in Auditory Hair Cells

et al. 2021

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“…The equivalent human mutant is dominant and linked to progressive hearing loss (Kurima et al 2002;Kitajiri et al 2007). We have shown that, from acoustic brainstem responses, both homozygotes and heterozygote Tmc1 p.D569N mice were completely deaf by P30 (Beurg et al 2019). However, early in neonatal development, MET currents were recordable from OHCs at P6 in Tmc1 p.D569N mice and such currents were not attributable to TMC2 because they were present in Tmc2 -/-.…”

Section: Tmc1 Pd569n Mutationmentioning

confidence: 99%

The contribution of TMC1 to adaptation of mechanoelectrical transduction channels in cochlear outer hair cells

Goldring

Beurg

Fettiplace

2019

The Journal of Physiology

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Key points Hair cell mechanoelectrical transducer channels are opened by deflections of the hair bundle about a resting position set by incompletely understood adaptation mechanisms. We used three characteristics to define adaptation in hair cell mutants of transmembrane channel‐like proteins, TMC1 and TMC2, which are considered to be channel constituents. The results obtained demonstrate that the three characteristics are not equivalent, and raise doubts about simple models in which intracellular Ca2+ regulates adaptation. Adaptation is faster and more effective in TMC1‐containing than in TMC2‐containing transducer channels. This result ties adaptation to the channel complex, and suggests that TMC1 is a better isoform for use in cochlear hair cells. We describe a TMC1 point mutation, D569N, that reduces the resting open probability and Ca2+ permeability of the transducer channels, comprising properties that may contribute to the deafness phenotype. Abstract Recordings of mechanoelectrical transducer (MET) currents in cochlear hair cells were made in mice with mutations of transmembrane channel‐like (TMC) protein to examine the effects on fast transducer adaptation. Adaptation was faster and more complete in Tmc2–/– than in Tmc1–/–, although this disparity was not explained by differences in Ca2+ permeability or Ca2+ influx between the two isoforms, with TMC2 having the larger permeability. We made a mouse mutation, Tmc1 p.D569N, homologous to a human DFNA36 deafness mutation, which also had MET channels with lower Ca2+‐permeability but showed better fast adaptation than wild‐type Tmc1+/+ channels. Consistent with the more effective adaptation in Tmc1 p.D569N, the resting probability of MET channel opening was smaller. The three TMC variants studied have comparable single‐channel conductances, although the lack of correlation between channel Ca2+ permeability and adaptation opposes the hypothesis that adaptation is controlled simply by Ca2+ influx through the channels. During the first postnatal week of mouse development, the MET currents amplitude grew, and transducer adaptation became faster and more effective. We attribute changes in adaptation partly to a developmental switch from TMC2‐ to TMC1‐ containing channels and partly to an increase in channel expression. More complete and faster adaptation, coupled with larger MET currents, may account for the sole use of TMC1 in the adult cochlear hair cells.

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