title: Effects of Cdh23 single nucleotide substitutions on age-related hearing loss in C57BL/6 and 129S1/Sv mice and comparisons with congenic strains.
abstract: A single nucleotide variant (SNV) of the cadherin 23 gene (Cdh23c.753A), common to many inbred mouse strains, accelerates age-related hearing loss (AHL) and can worsen auditory phenotypes of other mutations. We used homologous recombination in C57BL/6 NJ (B6N) and 129S1/SvImJ (129S1) embryonic stem cells to engineer mouse strains with reciprocal single base pair substitutions (B6-Cdh23c.753A>Gand 129S1-Cdh23c.753G>A). We compared ABR thresholds and cochlear pathologies of these SNV mice with those of congenic (B6.129S1-Cdh23Ahl+and 129S1.B6-Cdh23ahl) and parental (B6N and 129S1) strain mice. Results verified the protective effect of the Cdh23c.753Gallele, which prevented high frequency hearing loss in B6 mice to at least 18 months of age, and the AHL-inducing effect of the Cdh23c.753Aallele, which worsened hearing loss in 129S1 mice. ABR thresholds differed between 129S-Cdh23c.753ASNV and 129S1.B6-Cdh23ahlcongenic mice, and a linkage backcross involving these strains localized a Chr 10 QTL contributing to the difference. These results illustrate the large effects that strain background and congenic regions have on the hearing loss associated with Cdh23c.753alleles. Importantly, the B6-Cdh23c.753Gstrain can be used to eliminate the confounding influence of the Cdh23c.753Avariant in hearing studies of B6 mice and mutant mice on the B6 background.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Johnson
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors.forename: Cong
authors.initials: C
authors.lastname: Tian
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors.forename: Leona H
authors.initials: LH
authors.lastname: Gagnon
authors.affiliation: Center for Hearing and Deafness, University at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Center for Hearing and Deafness, University at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Dalian
authors.initials: D
authors.lastname: Ding
authors.affiliation: Center for Hearing and Deafness, University at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Salvi
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D001309:Auditory Threshold / Q000502:physiology; D015820:Cadherins / Q000172:deficiency / Q000235:genetics*; D003051:Cochlea / Q000378:metabolism* / Q000473:pathology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011304:Presbycusis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D040641:Quantitative Trait Loci; D013045:Species Specificity
chemical_list: D015820:Cadherins; C499091:Cdh23 protein, mouse