A Novel Mouse Model of MYO7A USH1B Reveals Auditory and Visual System Haploinsufficiencies

Abstract

Usher’s syndrome is the most common combined blindness–deafness disorder with USH1B, caused by mutations in MYO7A, resulting in the most severe phenotype. The existence of numerous, naturally occurring shaker1 mice harboring variable MYO7A mutations on different genetic backgrounds has complicated the characterization of MYO7A knockout (KO) and heterozygote mice. We generated a novel MYO7A KO mouse (Myo7a–/–) that is easily genotyped, maintained, and confirmed to be null for MYO7A in both the eye and inner ear. Like USH1B patients, Myo7a–/– 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. Myo7a–/– 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 Myo7a+/– mice had reduced numbers of cochlear HCs and concomitant reductions in auditory function relative to Myo7a+/+ controls. Notably, this is the first report that loss of a single Myo7a allele significantly alters auditory structure and function and suggests that audiological characterization of USH1B carriers is warranted. Maintenance of vestibular HCs in Myo7a–/– mice suggests that gene replacement could be used to correct the vestibular dysfunction in USH1B patients. While Myo7a–/– 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 MYO7A on a null background and generate valuable pre-clinical data toward the treatment of USH1B.

Usher syndrome type 1-associated gene, pcdh15b, is required for photoreceptor structural integrity in zebrafish

“…Specifically, although some deficiencies in vision have been reported, no mouse mutant has shown retinal degeneration/morphology defects unless exposed to altered light conditions (i.e. enhanced light/lack of pigmentation) ( Calabro et al, 2019 ; Haywood-Watson et al, 2006 ; Lentz et al, 2010 ; Libby and Steel, 2001 ; Libby et al, 2003 ; Peng et al, 2011 ; Trouillet et al, 2018 ; Williams et al, 2009 ). One possible explanation is that mice exhibit a photoreceptor structure that diverges from that of humans and other species ( El-Amraoui and Petit, 2014 ).…”

Functional Role of Class III Myosins in Hair Cells

“…Found on chromosome 11, the MYO7A gene encodes for a 250 kDa unconventional myosin that contains an N-terminal canonical myosin motor domain with a high duty ratio, five light-chain binding IQ motifs, and two MyTH4/FERM domains in its tail region, separated by an SH3 domain ( Figure 2 ; El-Amraoui et al, 2008 ; Heissler and Manstein, 2012 ). Due to its expression in both the calyceal processes and stereocilia, MYO7A mutations have been associated with both vision and hearing loss ( Calabro et al, 2019 ). Two distinct modes of hearing loss are commonly associated with MYO7A mutations, known as DFNA11 and DFNB2.…”

“…A mouse model of USH1B, known as shaker-1, contains a mutation in the MYO7A gene and displays both vision and hearing loss phenotypes ( Eudy and Sumegi, 1999 ). Interestingly, MYO7A (–/–) mice with no MYO7A expression have profound hearing and vision loss, displaying a loss of both inner and outer hair cells, though no loss in calyceal process structure or photoreceptor cells ( Calabro et al, 2019 ).…”

“…Amongst these proteins are various myosin motors, including the tip localizing MYO3A/B and MYO15A ( Figure 1B ), the tip-link associated MYO7A and MYO1C ( Figure 1C ), and the ankle tethering MYO6 ( Figure 1D ; Peng et al, 2011 ). Each motor is proposed to be important for different aspects of stereocilia morphology/function and thus loss of any individual myosin motor leads to stereocilia degeneration and hearing loss ( Lin et al, 2011 ; Rehman et al, 2016 ; Dantas et al, 2018 ; Calabro et al, 2019 ; Wang et al, 2019 ). Therefore, numerous studies have examined stereocilia-associated myosins providing crucial insight into their role in the hearing process.…”

Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy

“…Ewaso mice have the mutation p.I487N and have abnormal vestibular hair cells (Calabro et al, 2019). Dumbo mice have the mutation p.F947I and exhibit disorganized cochlear hair cells during development (Miller et al, 2012).…”