A Novel Mouse Model of USH1B Reveals Auditory and Visual System Haploinsufficiencies.

Usher's syndrome is the most common combined blindness-deafness disorder with USH1B, caused by mutations in , resulting in the most severe phenotype. The existence of numerous, naturally occurring mice harboring variable mutations on different genetic backgrounds has complicated the characterization of MYO7A knockout (KO) and heterozygote mice. We generated a novel MYO7A KO mouse ( ) that is easily genotyped, maintained, and confirmed to be null for MYO7A in both the eye and inner ear. Like USH1B patients, mice are profoundly deaf, and display near complete loss of inner and outer cochlear hair cells (HCs). No gross structural changes were observed in vestibular HCs. mice exhibited modest declines in retinal function but, unlike patients, no loss of retinal structure. We attribute the latter to differential expression of MYO7A in mouse vs. primate retina. Interestingly, heterozygous mice had reduced numbers of cochlear HCs and concomitant reductions in auditory function relative to controls. Notably, this is the first report that loss of a single allele significantly alters auditory structure and function and suggests that audiological characterization of USH1B carriers is warranted. Maintenance of vestibular HCs in mice suggests that gene replacement could be used to correct the vestibular dysfunction in USH1B patients. While mice do not exhibit sufficiently robust retinal phenotypes to be used as a therapeutic outcome measure, they can be used to assess expression of vectored on a null background and generate valuable pre-clinical data toward the treatment of USH1B.