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An MSM/Ms strain was established using Japanese wild mice, which exhibit resistance to several phenotypes associated with aging, such as obesity, inflammation, and tumorigenesis, compared to common inbred mouse strains. MSM/Ms strain is resistant to age-related hearing loss, and their auditory abilities are sustained for long durations. The age-related hearing loss 3 (ahl3) locus contributes to age-related hearing in MSM/Ms strain. We generated ahl3 congenic strains by transferring a genomic region on chromosome 17 from MSM/Ms mice into C57BL/6J mice. Although C57BL/6J mice develop age-related hearing loss because of the ahl allele of the cadherin 23 gene, the development of middle- to high-frequency hearing loss was significantly delayed in an ahl3 congenic strain. Moreover, the novel age-related hearing loss 10 (ahl10) locus associated with age-related hearing resistance in MSM/Ms strain was mapped to chromosome 12. Although the resistance effects in ahl10 congenic strain were slightly weaker than those in ahl3 congenic strain, slow progression of age-related hearing loss was confirmed in ahl10 congenic strain despite harboring the ahl allele of cadherin 23. These results suggest that causative genes and polymorphisms of the ahl3 and ahl10 loci are important targets for the prevention and treatment of age-related hearing loss. [ABSTRACT FROM AUTHOR]

• Myosin VI haploinsufficiency leads to mild hearing loss in mice. • Heterozygous myosin VI knockout mice developed age-related stereocilia fusion. • The outer hair cells of aged mice decreased due to myosin VI haploinsufficiency. • The ribbon synapses of aged mice were decreased due to myosin VI haploinsufficiency. In human, myosin VI (MYO6) haploinsufficiency causes postlingual progressive hearing loss. Because the usefulness of mouse models remains unclear, we produced novel Myo6 null (−/−) mutant mice and analyzed the hearing phenotypes of Myo6 +/− (+/−) heterozygous mutants. We first recorded and compared the auditory brainstem responses and distortion product otoacoustic emissions in control Myo6 +/+ (+/+) wild-type and +/− mice. These hearing phenotypes of +/− mice were mild; however, we confirmed that +/− mice developed progressive hearing loss. In particular, the hearing loss of female +/− mice progressed faster than that of male +/− mice. The stereocilia bundles of +/− mice exhibited progressive taper loss in cochlear inner hair cells (IHCs) and outer hair cells (OHCs). The loss of OHCs in +/− heterozygotes occurred at an earlier age than in +/+ mice. In particular, the OHCs at the basal area of the cochlea were decreased in +/− mice. IHC ribbon synapses from the area at the base of the cochlea were significantly reduced in +/− mice. Thus, our study indicated that MYO6 haploinsufficiency affected the detection of sounds in mice, and we suggest that +/− mice with Myo6 null alleles are useful animal models for gene therapy and drug treatment in patients with progressive hearing loss due to MYO6 haploinsufficiency. [ABSTRACT FROM AUTHOR]

The Rinshoken cataract ( rct) mutation, which causes congenital cataracts, is a recessive mutation found in SJL/J mice. All mutants present with opacity in the lens by 2 months of age. The rct locus was mapped to a 1.6-Mb region in Chr 4 that contains the Foxe3 gene. This gene is responsible for cataracts in humans and mice, and it plays a crucial role in the development of the lens. Furthermore, mutation of Foxe3 causes various ocular defects. We sequenced the genomic region of Foxe3, including the coding exons and UTRs; however, no mutations were discovered in these regions. Because there were no differences in Foxe3 sequences between the rct/ rct and wild-type mice, we inferred that a mutation was located in the regulatory regions of the Foxe3 gene. To test this possibility, we sequenced a 5′ noncoding region that is highly conserved among vertebrates and is predicted to be the major enhancer of Foxe3. This analysis revealed a deletion of 22-bp located approximately 3.2-kb upstream of the start codon of Foxe3 in rct mice. Moreover, we demonstrated by RT-PCR and in situ hybridization that the rct mutant has reduced expression of Foxe3 in the lens during development. We therefore suggest that cataracts in rct mice are caused by reduced Foxe3 expression in the lens and that this decreased expression is a result of a deletion in a cis-acting regulatory element. [ABSTRACT FROM AUTHOR]

The age-related hearing loss allele (Cdh23 ahl ) of the cadherin 23 gene leads to a more severe hearing loss phenotype through additive effects with risk alleles for hearing loss. In this study, we genome edited the Cdh23 ahl allele to the wild-type Cdh23 + allele in outbred ICR mice and inbred NOD/Shi mice established from ICR mice and investigated their effects on hearing phenotypes. Several hearing tests confirmed that ICR mice developed early onset high-frequency hearing loss and exhibited individual differences in hearing loss onset times. Severe loss of cochlear hair cells was also detected in the high-frequency areas in ICR mice. These phenotypes were rescued by genome editing the Cdh23 ahl allele to Cdh23 +, suggesting that abnormal hearing phenotypes develop because of the interaction of the Cdh23 ahl and risk alleles in the genetic background of ICR mice. NOD/Shi mice developed more severe hearing loss and hair cell degeneration than ICR mice. Hearing loss was detected at 1 month old. Hair cell loss, including degeneration of cell bodies and stereocilia, was observed in all regions of the cochlea in NOD/Shi mice. Although these phenotypes were partially rescued by genome editing to the Cdh23 + allele, the phenotypes associated with high-frequency hearing were mostly unrecovered in NOD/Shi mice. These results strongly suggest that the genetic background of NOD/Shi mice contain a potential risk allele for the acceleration of early onset high-frequency hearing loss. • Outbred ICR mice develop early onset high-frequency hearing loss (HFHL). • Cdh23 ahl allele-specific genome editing ameliorated early onset HFHL in ICR mice. • Inbred NOD/Shi mice of ICR origin developed early onset severe hearing loss. • HFHL in NOD/Shi mice was not rescued by Cdh23 ahl allele-specific genome editing. [ABSTRACT FROM AUTHOR]

The Foxe3 rct mutation, which causes early-onset cataracts, is a recessive mutation found in SJL/J mice. A previous study reported that cataract phenotypes are modified by the genetic background of mouse inbred strains and that the Pde6b rd1 mutation, which induced degeneration of the photoreceptor cells, is a strong candidate genetic modifier to accelerate the severity of cataractogenesis of Foxe3 rct mice. We created congenic mice by transferring a genomic region including the Foxe3 rct mutation to the B6 genetic background, which does not carry the Pde6b rd1 mutation. In the congenic mice, the cataract phenotypes became remarkably mild, and the development of cataracts was suppressed for a long time. Moreover, we created transgenic mice by injecting BAC clones including the wild-type Pde6b gene into the eggs of SJL- Foxe3 rct mice. Although the resistant effect for cataract phenotypes in transgenic mice was less than that in congenic mice, the severity and onset time of cataract phenotypes were clearly improved and delayed, respectively, compared with the phenotypes of the original SJL- Foxe3 rct mice. These results clearly show that the development of early-onset cataracts requires at least two mutant alleles of Foxe3 rct and Pde6b rd1 , and another modifier associated with the severity of cataract phenotypes in Foxe3 rct mice underlies the genetic backgrounds in mice. [ABSTRACT FROM AUTHOR]