Study on the Mechanism of Hearing Loss Induced by USH2A Gene Knockout

Usher syndrome (USH) is an autosomal recessive disorder characterized by hearing loss, retinitis pigmentosa, and variable vestibular dysfunction. USH2A is one of the causative genes of USH. This study is aimed at exploring the mechanism of hearing loss induced by USH2A gene knockout.

USH2A knockout (Ush2a^-/-) mice were used, and auditory brainstem response testing was performed on WT, Ush2a^-/-, and Ush2a^+/- mice. Then, the cochlea tissues were used to carry out immunofluorescence staining, hematoxylin and eosin (H&E) staining, and scanning electron microscopy (SEM). The mRNA expressions were detected by RT-qPCR. Finally, the differentially expressed genes (DEGs) in cochlear tissues of Ush2a^-/- and WT mice were identified by transcriptome sequencing.

Compared to WT mice, Ush2a^-/- and Ush2a^+/- mice exhibited moderate-to-severe nonprogressive hearing loss, with more pronounced deficits at low (4 kHz) and high (32/24 kHz) frequencies. HE staining and immunofluorescence staining showed that the modiolus, stria vascularis, basilar membrane, and the number of inner hair cells and outer hair cells (OHCs) in USH2A knockout mice have not changed. However, SEM results showed that severe stereociliary collapse was evident in OHCs of the Ush2a^-/- group. In addition, through transcriptomic analysis, 3632 upregulated genes and 2921 downregulated genes were obtained in the Ush2a^-/- mice. Among these DEGs, the most DEGs associated with hearing loss were Scn2a, Shank2, Bsn, Fcer1g, Prkce, Tgfb1, and Irf7.

This study demonstrates that USH2A deficiency disrupts auditory function through stereociliary instability and dysregulation of genes critical for synaptic transmission and cytoskeletal dynamics.