Genetic background effects on age-related hearing loss associated with Cdh23 variants in mice

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• 作者：Kelly L. Kane^a ; Chantal M. Longo-Guess^a ; Leona H. Gagnon^a ; Dalian Ding^b ; Richard J. Salvi^b ; Kenneth R. Johnson^a ; ^{ken.johnson@jax.org}
• 关键词：ABR ; auditory brainstem response ; AHL ; age-related hearing loss ; IHC ; inner hair cell ; OHC ; outer hair cell ; ANOVA ; analysis of variance ; st dev ; standard deviation ; SEM ; standard error of the mean
• 刊名：Hearing Research
• 出版年：2012
• 出版时间：January 2012
• 年：2012
• 卷：283
• 期：1-2
• 页码：80-88
• 全文大小：1094 K

文摘

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.