Accelerated Age-Related Degradation of the Tectorial Membrane in the Ceacam16 Null Mutant Mouse, a Model for Late-Onset Human Hereditary Deafness DFNB113.

CEACAM16 is a non-collagenous protein of the tectorial membrane, an extracellular structure of the cochlea essential for normal hearing. Dominant and recessive mutations in CEACAM16 have been reported to cause postlingual and progressive forms of deafness in humans. In a previous study of young Ceacam16 null mutant mice on a C57Bl/6J background, the incidence of spontaneous otoacoustic emissions (SOAEs) was greatly increased relative to Ceacam16 and Ceacam16 mice, but auditory brain-stem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were near normal, indicating auditory thresholds were not significantly affected. To determine if the loss of CEACAM16 leads to hearing loss at later ages in this mouse line, cochlear structure and auditory function were examined in Ceacam16, Ceacam16 and Ceacam16 mice at 6 and 12 months of age and compared to that previously described at 1 month. Analysis of older Ceacam16 mice reveals a progressive loss of matrix from the core of the tectorial membrane that is more extensive in the apical, low-frequency regions of the cochlea. In Ceacam16 mice at 6-7 months, the DPOAE magnitude at 2f1-f2 and the incidence of SOAEs both decrease relative to young animals. By ∼12 months, SOAEs and DPOAEs are not detected in Ceacam16 mice and ABR thresholds are increased by up to ∼40 dB across frequency, despite a complement of hair cells similar to that present in Ceacam16 mice. Although SOAE incidence decreases with age in Ceacam16 mice, it increases in aging heterozygous Ceacam16 mice and is accompanied by a reduction in the accumulation of CEACAM16 in the tectorial membrane relative to controls. An apically-biased loss of matrix from the core of the tectorial membrane, similar to that observed in young Ceacam16 mice, is also seen in Ceacam16 and Ceacam16 mice, and other strains of wild-type mice, but at much later ages. The loss of Ceacam16 therefore accelerates age-related degeneration of the tectorial membrane leading, as in humans with mutations in CEACAM16, to a late-onset progressive form of hearing loss.

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