Age-related degradation of tectorial membrane dynamics with loss of CEACAM16

Abstract

Studies of genetic disorders of sensorineural hearing loss have been instrumental in delineating mechanisms that underlie the remarkable sensitivity and selectivity that are hallmarks of mammalian hearing. For example, genetic modifications of TECTA and TECTB, which are principal proteins that comprise the tectorial membrane (TM), have been shown to alter auditory thresholds and frequency tuning in ways that can be understood in terms of changes in the mechanical properties of the TM. Here, we investigate effects of genetic modification targeting CEACAM16, a third important TM protein. Loss of CEACAM16 has been recently shown to lead to progressive reductions in sensitivity. Whereas age-related hearing losses have previously been linked to changes in sensory receptor cells, the role of the TM in progressive hearing loss is largely unknown. Here, we show that TM stiffness and viscosity are significantly reduced in adult mice that lack functional CEACAM16 relative to age-matched wild-type controls. By contrast, these same mechanical properties of TMs from juvenile mice that lack functional CEACAM16 are more similar to those of wild-type mice. Thus, changes in hearing phenotype align with changes in TM material properties and can be understood in terms of the same TM wave properties that were previously used to characterize modifications of TECTA and TECTB. These results demonstrate that CEACAM16 is essential for maintaining TM mechanical and wave properties, which in turn are necessary for sustaining the remarkable sensitivity and selectivity of mammalian hearing with increasing age.

Auditory Phenotype of a Novel Missense Variant in the CEACAM16 Gene in a Large Russian Family With Autosomal Dominant Nonsyndromic Hearing Loss

“…Thus, this experiment showed that the alteration of audiological phenotype corresponds with the changes in mechanical and wave properties of the TM, which are provided by the Ceacam16 protein. 12 This demonstrates the role of TM in the development of progressive late-onset hearing loss, which was previously associated with changes in sensory receptor cells only.…”

Nonsyndromic Deafness Due to A Peculiar Compound Heterozygous Genotype of Novel Nonsense and Missense CEACAM16 Variants

“…CEACAM16, previously described as carcinoembryonic antigen-related cell adhesion molecule 16, coding for a glycoprotein selectively expressed in the mammalian inner ear, secreted by cochlear outer hair cells of the organ of Corti, and localized to the tips of the tallest stereocilia and in the tectorial membrane (TM). In the TM, CEACAM16 interacts with other molecules such as glycoproteins α-tectorin (TECTA) and β-tectorin (TECTB), coded by TECTA and TECTB genes respectively, being a prominent component of TM's striated sheet structure relevant for hearing, resulting its targeted deletion in mice in patho-morphological TM defects and hearing loss [1][2][3][4]. Accordingly, CEACAM16 is a rare cause of NSHL in man, described in counted familial or in single cases, carriers of heterozygous or homozygous distinct sequence variants associated to dominant (ADNSHL; 1, 5-7) or recessive (ARNSHL) disease, also known as DFNA4B (Deafness, autosomal dominant 4B) and DFNB113 (Deafness, autosomal recessive 113) as referred in OMIM database (https://www.omim.org/entry/614591) [8][9][10].…”