Separate and combined effects of Sod1 and Cdh23 mutations on age-related hearing loss and cochlear pathology in C57BL/6J mice (original) (raw)
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A mutation in the cdh23 gene causes age-related hearing loss in Cdh23nmf308/nmf308 mice
Gene, 2012
Cadherin 23 (CDH23) is an important constituent of the hair cell tip link in the organ of Corti. Mutations in cdh23 are associated with age-related hearing loss (AHL). In this study, we proposed that the Cdh23 nmf308/nmf308 mice with progressive hair cell loss had specific morphological changes and suffered a base to apex gradient and age-related hearing loss, and that mutations in cdh23 were linked to AHL. The Cdh23 nmf308/nmf308 mice produced by the N-nitrosourea (ENU) mutagenesis program were used as an animal model to study AHL and progressive hair cell loss. RT-PCR was performed to confirm the cdh23 mutation in Cdh23 nmf308/nmf308 mice and genetic analysis was used to map the specific mutation site. Distortion product otoacoustic emission (DPOAE) assay and acoustic brainstem evoked response (ABR) threshold analysis were carried out to evaluate the AHL. Cochlear histology was examined with scanning electron microscope (SEM) and transmission electron microscope (TEM), as well as the nuclear labeling by propidium iodide staining; terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay and caspase-3 activities were examined to evaluate cell apoptosis. Genetic mapping identified the candidate gene linking AHL in Cdh23 nmf308/nmf308 mice as cdh23. A mutation in exon3 (63 T>C) was screened as compared with the sequence of the same position of the gene from B6 (+/+) mice. The cochleae outer hair cells were reduced from 5-10% at one month to 100% at three months in the basal region. DPOAE and ABR exhibited an increasing threshold at high frequencies (≥16 kHz) from one month of age. Morphological and cellular analysis showed that Cdh23 nmf308/nmf308 mice exhibited a time course of histological alterations and cell apoptosis of outer hair cells. Our results suggest that the cdh23 mutation may be harmful to the stereociliary tip link and cause the hair cell apoptosis. Due to the same cdh23 mutations in human subjects with presbycusis (Petit et al., 2001; Zheng et al., 2005), the Cdh23 nmf308/nmf308 mouse is an excellent animal model for investigating the mechanisms involved in human AHL.
Genetic background effects on age-related hearing loss associated with Cdh23 variants in mice
Hearing Research, 2012
Inbred strain variants of the Cdh23 gene have been shown to influence the onset and progression of agerelated 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 (Ahlþ) 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 Ahlþ 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 agematched 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 Ahlþ , 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 Ahlþ 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.
A locus on distal chromosome 10 (ahl4) affecting age-related hearing loss in A/J mice
Neurobiology of Aging, 2009
The ahl locus, shown to be a strain-specific Cdh23 dimorphism, contributes to age-related hearing loss in many inbred mouse strains. A/J mice begin to lose hearing by four weeks of age, much earlier than C57BL/6J (B6) mice, although both strains have the same Cdh23 ahl variant. Here, we use recombinant inbred strains, chromosome substitution strains, and a linkage backcross to map a locus on distal Chromosome 10, designated ahl4, that contributes to the early-onset hearing loss of A/J mice. Cochleae of 9-week-old A/J mice exhibit inner and outer hair cell loss from the basal turn through the apical turn, with outer hair cell loss at the base being severest. To quantify the progression of hair cell loss, cytocochleograms were evaluated from 0 to 20 weeks of age. AJ mice showed evidence of hair cell loss in the base of the cochlea as early as 14 days of age and the magnitude and extent of loss increased rapidly during the following 2-5 months. Hair cell loss occurred earlier and was much more severe and widespread in A/J mice than in B6 mice during the first 5 months of age. Spiral ganglion neurons, cells of the stria vascularis, and vestibular hair cell densities, however, appeared normal in 20-week-old A/J mice.
Mutations in Cdh23 Cause Nonsyndromic Hearing Loss in waltzer Mice
Genomics, 2001
Mutations at the waltzer (v) locus result in deafness and vestibular dysfunction due to degeneration of the neuroepithelium within the inner ear. Here, we use a positional cloning approach to show that waltzer encodes a novel cadherin (Cdh23), which is most closely related to the Drosophila Fat protein. A single nucleotide deletion in the v J allele and a single nucleotide insertion in the v allele are predicted to truncate each protein near the N-terminus and produce a functional null allele. In situ hybridization analysis showed that Cdh23 is expressed in the sensory hair cells of the inner ear, where it has been suggested to be a molecule critical for crosslinking of the stereocilia. In addition, Cdh23 is expressed in the urticulo-saccular foramen, the ductus reuniens, and Reissner's membrane, suggesting that Cdh23 may also be involved in maintaining the ionic composition of the endolymph. Finally, mutations in human CDH23 have recently been described for two loci, DFNB12 and USH1D, which cause nonsyndromic deafness, identifying waltzer as a mouse model for human hearing loss.
An Age-Related Hearing Protection Locus on Chromosome 16 of BXD Strain Mice
Neural Plasticity, 2020
Inbred mouse models are widely used to study age-related hearing loss (AHL). Many genes associated with AHL have been mapped in a variety of strains. However, little is known about gene variants that have the converse function—protective genes that confer strong resistance to hearing loss. Previously, we reported that C57BL/6J (B6) and DBA/2J (D2) strains share a common hearing loss allele in Cdh23. The cadherin 23 (Cdh23) gene is a key contributor to early-onset hearing loss in humans. In this study, we tested hearing across a large family of 54 BXD strains generated from B6 to D2 crosses. Five of 54 strains maintain the normal threshold (20 dB SPL) even at 2 years old—an age at which both parental strains are essentially deaf. Further analyses revealed an age-related hearing protection (ahp) locus on chromosome 16 (Chr 16) at 57~76 Mb with a maximum LOD of 5.7. A small number of BXD strains at 2 years with good hearing correspond roughly to the percentage of humans who have good h...
Scientific reports, 2017
A single nucleotide variant (SNV) of the cadherin 23 gene (Cdh23(c.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-Cdh23(c.753A>G) and 129S1-Cdh23(c.753G>A)). We compared ABR thresholds and cochlear pathologies of these SNV mice with those of congenic (B6.129S1-Cdh23(Ahl+) and 129S1.B6-Cdh23(ahl)) and parental (B6N and 129S1) strain mice. Results verified the protective effect of the Cdh23(c.753G) allele, which prevented high frequency hearing loss in B6 mice to at least 18 months of age, and the AHL-inducing effect of the Cdh23(c.753A) allele, which worsened hearing loss in 129S1 mice. ABR thresholds differed between 129S-Cdh23(c.753A) SNV and 129S1.B6-Cdh23(ahl) congenic mice, and a linkage backcross involving...
Cellular correlates of progressive hearing loss in 129S6/SvEv mice
The Journal of Comparative Neurology, 2004
Several strains of mice hear well initially but show progressive sensorineural hearing loss. Affected cochlear cell types include all those known to be affected in human age-related hearing loss (ARHL), or presbycusis. Thus these mice have been offered as models of human ARHL. At present, however, few mouse ARHL models are sufficiently well described to serve as the basis for specific hypotheses about human ARHL. We examined 1-month-old and 15-month-old 129S6/SvEv (129S6) mice and compared them with BALB/cJ and CBA/J mice. Age-related elevation of compound action potential thresholds was interpreted in the light of endocochlear potentials and changes in hair cells, afferent neurons, fibrocytes in spiral limbus and ligament, and supporting cells within the organ of Corti. Aging in 129S6 mice was associated with high-frequency hearing loss. Four components of age-related cochlear degeneration emerged from quantitative analyses, including 1) basal loss of outer hair cells; 2) basal loss of type IV fibrocytes in the spiral ligament; 3) apical loss of fibrocytes in spiral limbus, and 4) anomalies of supporting cells in the cochlear base. Although neuronal loss was not consistently found, two mice showed loss of afferent dendrites and cell bodies in the cochlear apex without inner hair cell loss. Despite multifaceted degeneration, hearing loss in 129S6 mice appears to be best explained by degenerative changes in outer hair cells and in the organ of Corti, conforming to human sensory ARHL. Age-related changes in the apical spiral limbus may promote pathology of the medial organ of Corti and eventual loss of afferent neurons, with possible implications for human neural ARHL.
Strain background effects and genetic modifiers of hearing in mice
Brain Research, 2006
Genetic modifiers can be detected in mice by looking for strain background differences in inheritance or phenotype of a mutation. They can be mapped by analyses of appropriate linkage crosses and congenic lines, and modifier genes of large effect can be identified by positionalcandidate gene testing. Inbred strains of mice vary widely in onset and severity of age-related hearing loss (AHL), an important consideration when assessing hearing in mutant mice. At least 8 mapped loci and a mitochondrial variant (mt-Tr) are known to contribute to AHL in mouse strains; one locus (ahl) has been identified as a variant of the cadherin 23 gene (Cdh23 753A/G). This variant also was shown to modify hearing loss associated with the Atp2b2 dfw-2J and Mass1 frings mutations. The hearing modifier (Moth1) of tubby (Tub tub) mutant mice was shown to be a strain variant of the Mtap1a gene. Human hearing modifiers include DFNM1, which suppresses recessive deafness DFNB26, and a nuclear gene that modulates the severity of hearing loss associated with a mitochondrial mutation. Recently, a variant of the human ATP2B2 gene was shown to exacerbate hearing loss in individuals homozygous for a CDH23 mutation, similar to the Atp2b2 dfw-2J-Cdh23 753A/G interaction affecting hearing in mice. Because modifier genes and digenic inheritance are not always distinguishable, we also include in this review several examples of digenic inheritance of hearing loss that have been reported in both mice and humans.
Human Molecular Genetics, 2008
Mutations in COCH (coagulation factor C homology) are etiologic for the late-onset, progressive, sensorineural hearing loss and vestibular dysfunction known as DFNA9. We introduced the G88E mutation by gene targeting into the mouse and have created a Coch G88E/G88E mouse model for the study of DFNA9 pathogenesis and cochlin function. Vestibular-evoked potential (VsEP) thresholds of Coch G88E/G88E mice were elevated at all ages tested compared with wild-type littermates. At the oldest ages, two out of eight Coch G88E/G88E mice had no measurable VsEP. Auditory brainstem response (ABR) thresholds of Coch G88E/G88E mice were substantially elevated at 21 months but not at younger ages tested. At 21 months, four of eight Coch G88E/G88E mice had absent ABRs at all frequencies tested and two of three Coch G88E/1 mice had absent ABRs at three of four frequencies tested. Distortion product otoacoustic emission amplitudes of Coch G88E/G88E mice were substantially lower than Coch 1/1 mice and absent in the same Coch G88E/G88E mice with absent ABRs. These results suggest that vestibular function is affected beginning as early as 11 months when cochlear function appears to be normal, and dysfunction increases with age. Hearing loss declines substantially at 21 months of age and progresses to profound hearing loss at some to all frequencies tested. This is the only mouse model developed to date where hearing loss begins at such an advanced age, providing an opportunity to study both progressive age-related hearing loss and possible interventional therapies.
Hearing Research, 2001
The modifier of deaf waddler (mdfw) and age-related hearing loss (Ahl) loci were both discovered as inbred strain polymorphisms that affect hearing loss in mice. Both loci map to the same position on chromosome (Chr) 10. The mdfw locus interacts epistatically with the deaf waddler (dfw) mutation on Chr 6, and the Ahl locus is a major contributor to AHL in several inbred strains. To investigate the possibility of allelism, we examined the correspondence of mdfw and Ahl phenotypes among 12 inbred mouse strains. The effects of strain-specific mdfw alleles on hearing loss were assessed in dfw 2J /+ F1 hybrids produced from mating BALB-dfw 2J /+ mice with mice from each of 12 inbred strains. F1 hybrids were then assessed for hearing by auditory-evoked brainstem response threshold analysis and classified as dfw 2J /+ or +/+ by polymerase chain reaction typing. Heterozygosity for dfw 2J accelerated hearing loss in F1 hybrids derived from all strains tested, except those produced with the B6.CAST + Ahl congenic strain. dfw 2J /+ F1 hybrids derived from parental strains 129P1/ ReJ, A/J, BUB/BnJ, C57BR/cdJ, DBA/2J, NOD/LtJ and SKH2/J exhibited a severe hearing loss by 12 weeks of age. Those derived from strains 129T2/SvEmsJ, C3H/HeJ, CBA/CaJ and NON/LtJ exhibited only a slight to intermediate hearing loss at that age. The hearing loss associated with these strain-specific mdfw alleles corresponds with previously determined Ahl allele effects, providing additional evidence that mdfw and Ahl are manifestations of the same gene. A functional relationship therefore may exist between the Ca 2+ transporting activity of the dfw gene (Atp2b2) and AHL.