Abstract
Myo3a is expressed in cochlear hair cells and retinal cells and is responsible for human recessive hereditary nonsyndromic deafness (DFNB30). To investigate the mechanism of DFNB30-type deafness, we established a mouse model of Myo3a kinase domain Y137C mutation by using CRISPR/Cas9 system. No difference in hearing between 2-month-old Myo3a mutant mice and wild-type mice was observed. The hearing threshold of the ≥6-month-old mutant mice was significantly elevated compared with that of the wild-type mice. We observed degeneration in the inner ear hair cells of 6-month-old Myo3a mutant mice, and the degeneration became more severe at the age of 12 months. We also found structural abnormality in the cochlear hair cell stereocilia. Our results showed that Myo3a is essential for normal hearing by maintaining the intact structure of hair cell stereocilia, and the kinase domain plays a critical role in the normal functions of Myo3a. This mouse line is an excellent model for studying DFNB30-type deafness in humans.
Highlights
Deafness presents the highest incidence among sensory defects
To mimic Myo3a Y129C mutation in human, we introduced the A410G (Y137C) mutation in mice by using CRISPR/Cas9 technology (Figure 1)
The sgRNA containing the 20 bp target sequence complexed with Cas9 protease can introduce double-strand break (DSB) into the target sequence near a protospacer-adjacent motif (PAM) sequence
Summary
Deafness presents the highest incidence among sensory defects. One-third of the global population suffer from hearing impairment. Presbyacusis, known as age-related hearing loss (ARHL), refers to the gradual onset of sensorineural hearing loss with age. According to WHO statistics, over one-third of the >65-year-old population are currently affected by senile deafness. Senile deafness is related to environmental factors, such as disease, ear-toxic drugs, noise, and mental trauma, and genetic factors play an important role in this process. 50% of age-related deafness is determined by genetic factors [7]. Senile deafness is a complex disease that can be affected by a variety of environmental factors, and differences in the genetic background of different populations can interfere with research. The use of gene knock-out/knockin mouse model can strictly control environmental conditions and reduce the influence of genetic background, thereby providing important tools for the validation of ageand deafness-related genes. The establishment of presbyacusis animal model has become an important method in studying presbyacusis
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