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Inbred strain variants of the Cdh23 gene have been shown to influence the onset and progression of age-related hearing loss (AHL) in mice. In linkage backcrosses, the recessive Cdh23 allele (ahl) of the C57BL/6J strain, when homozygous, confers increased susceptibility to AHL, while the dominant allele (Ahl+) of the CBA/CaJ strain confers resistance. To determine the isolated effects of these alleles on different strain backgrounds, we produced the reciprocal congenic strains B6.CBACa-Cdh23(Ahl)(+) and CBACa.B6-Cdh23(ahl) and tested 15-30 mice from each for hearing loss progression. ABR thresholds for 8 kHz, 16 kHz, and 32 kHz pure-tone stimuli were measured at 3, 6, 9, 12, 15 and 18 months of age and compared with age-matched mice of the C57BL/6J and CBA/CaJ parental strains. Mice of the C57BL/6N strain, which is the source of embryonic stem cells for the large International Knockout Mouse Consortium, were also tested for comparisons with C57BL/6J mice. Mice of the C57BL/6J and C57BL/6N strains exhibited identical hearing loss profiles: their 32 kHz ABR thresholds were significantly higher than those of CBA/CaJ and congenic strain mice by 6 months of age, and their 16 kHz thresholds were significantly higher by 12 months. Thresholds of the CBA/CaJ, the B6.CBACa-Cdh23(Ahl)(+), and the CBACa.B6-Cdh23(ahl) strain mice differed little from one another and only slightly increased throughout the 18-month test period. Hearing loss, which corresponded well with cochlear hair cell loss, was most profound in the C57BL/6J and C57BL/6NJ strains. These results indicate that the CBA/CaJ-derived Cdh23(Ahl)(+) allele dramatically lessens hearing loss and hair cell death in an otherwise C57BL/6J genetic background, but that the C57BL/6J-derived Cdh23(ahl) allele has little effect on hearing loss in an otherwise CBA/CaJ background. We conclude that although Cdh23(ahl) homozygosity is necessary, it is not by itself sufficient to account for the accelerated hearing loss of C57BL/6J mice., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Both the ahl allele of Cdh23 and the null mutation of Sod1 have been shown to contribute to age-related hearing loss (AHL) in mice, but mixed strain backgrounds have confounded analyses of their individual and combined effects. To test for the effects of Sod1 deficiency independently from those of Cdh23(ahl), we produced mice with four digenic genotypes: Sod1(+/+)Cdh23(ahl)(/ahl), Sod1(+/+)Cdh23(+/+), Sod1(-/-)Cdh23(ahl)(/ahl), and Sod1(-/-)Cdh23(+/+), all on a uniform C57BL(/)6J strain background. We assessed hearing loss by ABR threshold measurements and evaluated cochlear pathologies in age-matched mice of each digenic combination. ABR analysis showed that Sod1(+/+)Cdh23(+/+) mice retain normal hearing up to 15 months of age and that hearing loss of Sod1(+/+)Cdh23(ahl)(/ahl) mice is more age and frequency dependent than that of Sod1(-/-)Cdh23(+/+) mice. ABR results also showed that mice with both gene mutations (Sod1(-/-)Cdh23(ahl)(/ahl)) exhibit the earliest onset and most severe hearing loss, greater than predicted for strictly additive effects. Histological analysis of cochleas showed that hair cell lesions are most severe in Sod1(-)(/-)Cdh23(ahl)(/ahl) mice followed closely by Sod1(+)(/+)Cdh23(ahl)(/ahl) mice and much smaller in Sod1(-)(/-)Cdh23(+)(/+) and Sod1(+)(/+)Cdh23(+)(/+) mice. Despite extensive damage to cochlear hair cells, vestibular hair cells appeared remarkably normal in all strains. Although both Sod1(-/-) and Cdh23(ahl)(/ahl) genotypes had strong effects on hearing loss, the Cdh23(ahl/ahl) genotype was primarily responsible for the increase in hair cell loss, suggesting that the two mutations have different underlying mechanisms of pathology., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Mutations of the otoferlin gene have been shown to underlie deafness disorders in humans and mice. Analyses of genetically engineered mice lacking otoferlin have demonstrated an essential role for this protein in vesicle exocytosis at the inner hair cell afferent synapse. Here, we report on the molecular and phenotypic characterization of a new ENU-induced missense mutation of the mouse otoferlin gene designated Otof(deaf5Jcs). The mutation is a single T to A base substitution in exon 10 of Otof that causes a non-conservative amino acid change of isoleucine to asparagine in the C2B domain of the protein. Although strong immunoreactivity with an otoferlin-specific antibody was detected in cochlear hair cells of wildtype mice, no expression was detected in mutant mice, indicating that the missense mutation has a severe effect on the stability of the protein and potentially its localization. Auditory brainstem response (ABR) analysis demonstrated that mice homozygous for the missense mutation are profoundly deaf, consistent with an essential role for otoferlin in inner hair cell neurotransmission. Vestibular-evoked potentials (VsEPs) of mutant mice, however, were equivalent to those of wildtype mice, indicating that otoferlin is unnecessary for vestibular function even though it is highly expressed in both vestibular and cochlear hair cells.