Loss of the Tectorial Membrane Protein CEACAM16 Enhances Spontaneous, Stimulus-Frequency, and Transiently Evoked Otoacoustic Emissions

Cheatham, Mary Ann; Goodyear, Richard J.; Homma, Kazuaki; Legan, P. Kevin; Korchagina, Julia; Naskar, Souvik; Siegel, Jonathan H.; Dallos, Peter; Zheng, Jing; Richardson, Guy P.

doi:10.1523/jneurosci.1256-14.2014

Cited by 62 publications

(89 citation statements)

References 68 publications

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“…Mouse experiments demonstrate that TECTB is directly influenced by CEACAM16 because loss of CEACAM16 reduces the level of TECTB and the striated-sheet matrix and Hensen's stripe remain immature [Cheatham et al, 2014]. Additionally, TECTA is undetectable after postnatal day 22 [Rau et al, 1999].…”

Section: Predicted Effect Of the C1094t>g Mutation On Protein Interamentioning

confidence: 99%

“…This is a plausible explanation why hearing loss occurs at a later stage and is progressive. Moreover, this could explain why there were neither hearing nor anatomical differences between wild-type mice and Ceacam16 heterozygotes, which were both clearly identified in homozygous mice [Cheatham et al, 2014] because the knock out mouse elicited the reduced expression that resulted in hearing loss. Furthermore, hearing loss could be influenced according to the affected domain.…”

Section: Predicted Effect Of the C1094t>g Mutation On Protein Interamentioning

confidence: 99%

“…1 c) and is predicted by MutationAssessor to affect a protein binding site. This could be a binding site for TECTB and TECTA crosslinking with CEACAM16 for developing the striated-sheet matrix structure [Cheatham et al, 2014]. The N2 domain has homophilic interactions and forms dimers for supporting cell adhesion.…”

Section: Predicted Effect Of the C1094t>g Mutation On Protein Interamentioning

confidence: 99%

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A Novel de novo Mutation in CEACAM16 Associated with Postlingual Hearing Impairment

Hofrichter¹,

Nanda²,

Gräf³

et al. 2015

Mol Syndromol

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Mutations in CEACAM16 cause autosomal dominant nonsyndromic hearing loss (DFNA4B). So far, 2 families have been reported with segregating missense mutations, both in the immunoglobulin constant domain A of the CEACAM16 protein. In this study, we used the TruSight One panel to investigate a parent-child trio without familial history of hearing loss and one affected child. When filtering for recessive inheritance and de novo events, we discovered a de novo CEACAM16 mutation (c.1094T>G, p.Leu365Arg) as the sole likely pathogenic variant. The de novo mutation was confirmed by Sanger sequencing and STR analysis. The proband's hearing loss closely matches the described onset and severity for DFNA4B. We present the third CEACAM16 variant and the first de novo mutation in CEACAM16. This de novo mutation is robustly described as a pathogenic mutation according to in silico mutation prediction tools and affects a highly conserved amino acid in the most strongly conserved CEACAM16 N2 domain. Our strategy of screening family trios enhances de novo mutation discovery and the exclusion of other variants of potential interest through pedigree filtering.

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Section: Predicted Effect Of the C1094t>g Mutation On Protein Interamentioning

confidence: 99%

Section: Predicted Effect Of the C1094t>g Mutation On Protein Interamentioning

confidence: 99%

Section: Predicted Effect Of the C1094t>g Mutation On Protein Interamentioning

confidence: 99%

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A Novel de novo Mutation in CEACAM16 Associated with Postlingual Hearing Impairment

Hofrichter¹,

Nanda²,

Gräf³

et al. 2015

Mol Syndromol

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“…CEACAM-16 is a third glycoprotein in the tectorial membrane, and it is thought to interact with both α-tectorin and β-tectorin. In the absence of CEACAM-16, there is loss of the striate-sheet matrix but an increase in activity, as indicated by spontaneous otoacoustic emissions (37). This observation supports a role for the tectorial membrane in the mechanical sensitivity and stability of the cochlea.…”

Section: Frequency Tuningmentioning

confidence: 99%

Hair Cell Transduction, Tuning, and Synaptic Transmission in the Mammalian Cochlea

Fettiplace

2017

Comprehensive Physiology

270

273

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Sound pressure fluctuations striking the ear are conveyed to the cochlea, where they vibrate the basilar membrane on which sit hair cells, the mechanoreceptors of the inner ear. Recordings of hair cell electrical responses have shown that they transduce sound via sub-micrometer deflections of their hair bundles, which are arrays of interconnected stereocilia containing the mechanoelectrical transducer (MET) channels. MET channels are activated by tension in extracellular tip links bridging adjacent stereocilia, and they can respond within microseconds to nanometer displacements of the bundle, facilitated by multiple processes of Ca2+-dependent adaptation. Studies of mouse mutants have produced much detail about the molecular organization of the stereocilia, the tip links and their attachment sites, and the MET channels localized to the lower ends of each tip link. The mammalian cochlea contains two categories of hair cells. Inner hair cells relay acoustic information via multiple ribbon synapses that transmit rapidly without rundown. Outer hair cells are important for amplifying sound-evoked vibrations. The amplification mechanism primarily involves contractions of the outer hair cells, which are driven by changes in membrane potential and mediated by prestin, a motor protein in the outer hair cell lateral membrane. Different sound frequencies are separated along the cochlea, with each hair cell being tuned to a narrow frequency range; amplification sharpens the frequency resolution and augments sensitivity 100-fold around the cell’s characteristic frequency. Genetic mutations and environmental factors such as acoustic overstimulation cause hearing loss through irreversible damage to the hair cells or degeneration of inner hair cell synapses.

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“…For example, whether Hensen's stripe is connected to the IHC stereocilia is unclear (35,80). In mice, the Hensen's stripe was not observed in apical (low frequency) locations of the cochlea as it was in basal locations (81).…”

Section: Limitations Of This Study-the Importance Of Sts Anatomymentioning

confidence: 99%

Power Dissipation in the Subtectorial Space of the Mammalian Cochlea Is Modulated by Inner Hair Cell Stereocilia

Prodanovic

Gracewski

Nam

2015

Biophysical Journal

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The stereocilia bundle is the mechano-transduction apparatus of the inner ear. In the mammalian cochlea, the stereocilia bundles are situated in the subtectorial space (STS)--a micrometer-thick space between two flat surfaces vibrating relative to each other. Because microstructures vibrating in fluid are subject to high-viscous friction, previous studies considered the STS as the primary place of energy dissipation in the cochlea. Although there have been extensive studies on how metabolic energy is used to compensate the dissipation, much less attention has been paid to the mechanism of energy dissipation. Using a computational model, we investigated the power dissipation in the STS. The model simulates fluid flow around the inner hair cell (IHC) stereocilia bundle. The power dissipation in the STS because of the presence IHC stereocilia increased as the stimulating frequency decreased. Along the axis of the stimulating frequency, there were two asymptotic values of power dissipation. At high frequencies, the power dissipation was determined by the shear friction between the two flat surfaces of the STS. At low frequencies, the power dissipation was dominated by the viscous friction around the IHC stereocilia bundle--the IHC stereocilia increased the STS power dissipation by 50- to 100-fold. There exists a characteristic frequency for STS power dissipation, CFSTS, defined as the frequency where power dissipation drops to one-half of the low frequency value. The IHC stereocilia stiffness and the gap size between the IHC stereocilia and the tectorial membrane determine the characteristic frequency. In addition to the generally assumed shear flow, nonshear STS flow patterns were simulated. Different flow patterns have little effect on the CFSTS. When the mechano-transduction of the IHC was tuned near the vibrating frequency, the active motility of the IHC stereocilia bundle reduced the power dissipation in the STS.

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Loss of the Tectorial Membrane Protein CEACAM16 Enhances Spontaneous, Stimulus-Frequency, and Transiently Evoked Otoacoustic Emissions

Cited by 62 publications

References 68 publications

A Novel de novo Mutation in CEACAM16 Associated with Postlingual Hearing Impairment

A Novel de novo Mutation in CEACAM16 Associated with Postlingual Hearing Impairment

Hair Cell Transduction, Tuning, and Synaptic Transmission in the Mammalian Cochlea

Power Dissipation in the Subtectorial Space of the Mammalian Cochlea Is Modulated by Inner Hair Cell Stereocilia

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