Loss of Mammal-specific Tectorial Membrane Component Carcinoembryonic Antigen Cell Adhesion Molecule 16 (CEACAM16) Leads to Hearing Impairment at Low and High Frequencies

Kammerer, Robert; Rüttiger, Lukas; Riesenberg, Rainer; Schäuble, Constanze; Krupar, Rosemarie; Kamp, Annegret; Sunami, Kishiko; Eisenried, Andreas; Hennenberg, Martin; Fritz, Günter; Bress, Andreas; Battaglia, Sebastiano; Schrewe, Heinrich; Knipper, Marlies; Schneider, Marlon R.; Zimmermann, Wolfgang

doi:10.1074/jbc.m111.320481

Cited by 41 publications

(50 citation statements)

References 39 publications

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“…Even though the stereocilia of the cochlear inner hair cells (IHCs) appear to be free standing (Lim 1971;Dallos et al 1972), the TM is also thought to facilitate their stimulation (Dallos et al 1972;Richardson et al 2008;Lukashkin et al 2010). The body of the TM contains collagen fibrils embedded in an unusual striated-sheet matrix, the major components of which are alpha and betatectorin (Tecta and Tectb, respectively) and Ceacam16 (Legan et al 1997;Zheng et al 2011;Kammerer et al 2012;Cheatham et al 2014). In the absence of functional Tecta, the TM becomes completely de-tached from the organ of Corti and the animals suffer a significant hearing loss (Legan et al 2000;MorenoPelayo et al 2008;Legan et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Increased Spontaneous Otoacoustic Emissions in Mice with a Detached Tectorial Membrane

Cheatham¹,

Ahmad²,

Zhou³

et al. 2015

JARO

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Mutations in genes encoding tectorial membrane (TM) proteins are a significant cause of human hereditary hearing loss , and several mouse models have been developed to study the functional significance of this accessory structure in the mammalian cochlea. In this study, we use otoacoustic emissions (OAE), signals obtained from the ear canal that provide a measure of cochlear function, to characterize a mouse in which the TM is detached from the spiral limbus due to an absence of otoancorin (Otoa, Lukashkin et al. 2012). Our results demonstrate that spontaneous emissions (SOAE), sounds produced in the cochlea without stimulation, increase dramatically in mice with detached TMs even though their hearing sensitivity is reduced. This behavior is unusual because wild-type (WT) controls are rarely spontaneous emitters. SOAEs in mice lacking Otoa predominate around 7 kHz, which is much lower than in either WT animals when they generate SOAEs or in mutant mice in which the TM protein Ceacam16 is absent (Cheatham et al. 2014). Although both mutants lack Hensen's stripe, loss of this TM feature is only observed in regions coding frequencies greater than~15 kHz in WT mice so its loss cannot explain the low-frequency, de novo SOAEs observed in mice lacking Otoa. The fact that~80 % of mice lacking Otoa produce SOAEs even when they generate smaller distortion product OAEs suggests that the active process is still functioning in these mutants but the system(s) involved have become less stable due to alterations in TM structure.

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Section: Introductionmentioning

confidence: 99%

Increased Spontaneous Otoacoustic Emissions in Mice with a Detached Tectorial Membrane

Cheatham¹,

Ahmad²,

Zhou³

et al. 2015

JARO

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“…Of the noncollagenous proteins, TECTA and TECTB dominate the proteinaceous content, but their mRNA is not expressed after about postnatal day 22 (P22; Rau et al, 1999), making it difficult to conceive how the TM is maintained throughout life. In contrast, Ceacam16 mRNA expression is observed by P10 and the protein is distributed throughout the TM by P18 (Kammerer et al, 2012). Ceacam16 mRNA expression is maintained in older animals (Kammerer et al, 2012), and the continuous production of CEACAM16 may stabilize TECTA in the TM of adults because the two proteins are known to interact (Zheng et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, Ceacam16 mRNA expression is observed by P10 and the protein is distributed throughout the TM by P18 (Kammerer et al, 2012). Ceacam16 mRNA expression is maintained in older animals (Kammerer et al, 2012), and the continuous production of CEACAM16 may stabilize TECTA in the TM of adults because the two proteins are known to interact (Zheng et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…The secreted glycoprotein CEACAM16 is present in the cochlea, where it is observed in supporting cells, interdental cells of the limbus, and, principally, in the tectorial membrane (TM), an accessory structure overlying the organ of Corti (Zheng et al, 2011;Kammerer et al, 2012). We showed recently (Zheng et al, 2011) that the Ceacam16 gene is mutated in American Family 1070, a family with a hearing loss that begins in adolescence and progresses with age to an ϳ50 dB threshold shift, a decrease in sensitivity consistent with a loss of cochlear amplification (Chen et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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

Cheatham

Goodyear

Homma

et al. 2014

Journal of Neuroscience

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␣-Tectorin (TECTA), ␤-tectorin (TECTB), and carcinoembryonic antigen-related cell adhesion molecule 16 (CEACAM) are secreted glycoproteins that are present in the tectorial membrane (TM), an extracellular structure overlying the hearing organ of the inner ear, the organ of Corti. Previous studies have shown that TECTA and TECTB are both required for formation of the striated-sheet matrix within which collagen fibrils of the TM are imbedded and that CEACAM16 interacts with TECTA. To learn more about the structural and functional significance of CEACAM16, we created a Ceacam16-null mutant mouse. In the absence of CEACAM16, TECTB levels are reduced, a clearly defined striated-sheet matrix does not develop, and Hensen's stripe, a prominent feature in the basal two-thirds of the TM in WT mice, is absent. CEACAM16 is also shown to interact with TECTB, indicating that it may stabilize interactions between TECTA and TECTB. Although brain-stem evoked responses and distortion product otoacoustic emissions are, for most frequencies, normal in young mice lacking CEACAM16, stimulus-frequency and transiently evoked emissions are larger. We also observed spontaneous otoacoustic emissions (SOAEs) in 70% of the homozygous mice. This incidence is remarkable considering that Ͻ3% of WT controls have SOAEs. The predominance of SOAEs Ͼ15 kHz correlates with the loss of Hensen's stripe. Results from mice lacking CEACAM16 are consistent with the idea that the organ of Corti evolved to maximize the gain of the cochlear amplifier while preventing large oscillations. Changes in TM structure appear to influence the balance between energy generation and dissipation such that the system becomes unstable.

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“…The interdental cells have a role in the deposition of the tectorial membrane and deficits in the production of key structural proteins by these cells, such as CEACAM16, can lead to SNHL. 29 Similarly, Pillar cells and Deiters' cells create a rigid scaffold made of actin and microtubule bundles that support and surround the outer hair cells and facilitate an appropriate level of mechanical loading. These cells have been shown to be linked to the overall electromotility of the outer hair cell units, which can be impaired by the loss of the gap junction protein connexin 26, leading to SNHL.…”

Section: Discussionmentioning

confidence: 99%

The role of GTF2IRD1 in the auditory pathology of Williams–Beuren Syndrome

et al. 2014

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Williams-Beuren Syndrome (WBS) is a rare genetic condition caused by a hemizygous deletion involving up to 28 genes within chromosome 7q11.23. Among the spectrum of physical and neurological defects in WBS, it is common to find a distinctive response to sound stimuli that includes extreme adverse reactions to loud, or sudden sounds and a fascination with certain sounds that may manifest as strengths in musical ability. However, hearing tests indicate that sensorineural hearing loss (SNHL) is frequently found in WBS patients. The functional and genetic basis of this unusual auditory phenotype is currently unknown. Here, we investigated the potential involvement of GTF2IRD1, a transcription factor encoded by a gene located within the WBS deletion that has been implicated as a contributor to the WBS assorted neurocognitive profile and craniofacial abnormalities. Using Gtf2ird1 knockout mice, we have analysed the expression of the gene in the inner ear and examined hearing capacity by evaluating the auditory brainstem response (ABR) and the distortion product of otoacoustic emissions (DPOAE). Our results show that Gtf2ird1 is expressed in a number of cell types within the cochlea, and Gtf2ird1 null mice showed higher auditory thresholds (hypoacusis) in both ABR and DPOAE hearing assessments. These data indicate that the principal hearing deficit in the mice can be traced to impairments in the amplification process mediated by the outer hair cells and suggests that similar mechanisms may underpin the SNHL experienced by WBS patients.

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Loss of Mammal-specific Tectorial Membrane Component Carcinoembryonic Antigen Cell Adhesion Molecule 16 (CEACAM16) Leads to Hearing Impairment at Low and High Frequencies

Cited by 41 publications

References 39 publications

Increased Spontaneous Otoacoustic Emissions in Mice with a Detached Tectorial Membrane

Increased Spontaneous Otoacoustic Emissions in Mice with a Detached Tectorial Membrane

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

The role of GTF2IRD1 in the auditory pathology of Williams–Beuren Syndrome

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