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

• Published in: The Journal of biological chemistry 2012-06, Vol.287 (26), p.21584-21598
• Main Authors: Kammerer, Robert, Rüttiger, Lukas, Riesenberg, Rainer, Schäuble, Constanze, Krupar, Rosemarie, Kamp, Annegret, Sunami, Kishiko, Eisenried, Andreas, Hennenberg, Martin, Grunert, Fritz, Bress, Andreas, Battaglia, Sebastiano, Schrewe, Heinrich, Knipper, Marlies, Schneider, Marlon R., Zimmermann, Wolfgang
• Format: Article
• Language: English
• Subjects: Animal Models; Animals; Carcinoembryonic Antigen; Cell Adhesion Molecules - biosynthesis; Cell Adhesion Molecules - genetics; Cochlea; Cochlea - metabolism; Deafness; Development; Electrophysiology; Extracellular Matrix Proteins - metabolism; Female; GPI-Linked Proteins - metabolism; Hair Cells, Auditory - metabolism; Hearing; Hearing Loss - genetics; Hearing Loss - metabolism; Humans; Inner Ear; Knock-out; Male; Membrane Proteins - metabolism; Mice; Mice, Transgenic; Molecular Bases of Disease; Mutation; Myosin Heavy Chains - genetics; Myosin Type II - genetics; Recombination, Genetic; Tectorial Membrane; Tectorial Membrane - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.320481

The vertebrate-restricted carcinoembryonic antigen gene family evolves extremely rapidly. Among their widely expressed members, the mammal-specific, secreted CEACAM16 is exceptionally well conserved and specifically expressed in the inner ear. To elucidate a potential auditory function, we inactivated murine Ceacam16 by homologous recombination. In young Ceacam16−/− mice the hearing threshold for frequencies below 10 kHz and above 22 kHz was raised. This hearing impairment progressed with age. A similar phenotype is observed in hearing-impaired members of Family 1070 with non-syndromic autosomal dominant hearing loss (DFNA4) who carry a missense mutation in CEACAM16. CEACAM16 was found in interdental and Deiters cells and was deposited in the tectorial membrane of the cochlea between postnatal days 12 and 15, when hearing starts in mice. In cochlear sections of Ceacam16−/− mice tectorial membranes were significantly more often stretched out as compared with wild-type mice where they were mostly contracted and detached from the outer hair cells. Homotypic cell sorting observed after ectopic cell surface expression of the carboxyl-terminal immunoglobulin variable-like N2 domain of CEACAM16 indicated that CEACAM16 can interact in trans. Furthermore, Western blot analyses of CEACAM16 under reducing and non-reducing conditions demonstrated oligomerization via unpaired cysteines. Taken together, CEACAM16 can probably form higher order structures with other tectorial membrane proteins such as α-tectorin and β-tectorin and influences the physical properties of the tectorial membrane. Evolution of CEACAM16 might have been an important step for the specialization of the mammalian cochlea, allowing hearing over an extended frequency range. Genes evolved in mammals for specialization of hearing. CEA cell adhesion molecule 16 (CEACAM16) is a structural component of the tectorial membrane and necessary for hearing at low and high frequencies. CEACAM16 has evolved in mammals to broaden the auditory frequency range. Mutation of CEACAM16 is responsible for human autosomal dominant hearing loss (DFNA4).