title: Genetic background effects on age-related hearing loss associated with Cdh23 variants in mice.
abstract: 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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, 600 Main Street, ME 04609, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Kane
authors.forename: Chantal M
authors.initials: CM
authors.lastname: Longo-Guess
authors.forename: Leona H
authors.initials: LH
authors.lastname: Gagnon
authors.forename: Dalian
authors.initials: D
authors.lastname: Ding
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Salvi
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Johnson
mesh_terms: D000161:Acoustic Stimulation; D000367:Age Factors; D000375:Aging; D000818:Animals; D001301:Audiometry, Pure-Tone; D001309:Auditory Threshold; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D003051:Cochlea / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem; D005260:Female; D020022:Genetic Predisposition to Disease; D006198:Hair Cells, Auditory / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011304:Presbycusis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013045:Species Specificity
chemical_list: D015820:Cadherins; C499091:Cdh23 protein, mouse