Knockout of ush2a gene in zebrafish causes hearing impairment and late onset rod-cone dystrophy

AbstractMost cases of Usher syndrome type II (USH2) are due to mutations in theUSH2A gene. There are no effective treatments or ideal animal models for this disease, and the pathological mechanisms of USH2 caused byUSH2A mutations are still unknown. Here, we constructed aush2a knockout (ush2a−/−) zebrafish model using TALEN technology to investigate the molecular pathology of USH2. An early onset auditory disorder and abnormal morphology of inner ear stereocilia were identified in theush2a−/− zebrafish. Consequently, the disruption of Ush2a in zebrafish led to a hearing impairment, like that in mammals. Electroretinography (ERG) test indicated that deletion of Ush2a affected visual function at an early stage, and histological analysis revealed that the photoreceptors progressively degenerated. Rod degeneration occurred prior to cone degeneration inush2a−/− zebrafish, which is consistent with the classical description of the progression of retinitis pigmentosa (RP). Destruction of the outer segments (OSs) of rods led to the down-regulation of phototransduction cascade proteins at late stage. The expression of Ush1b and Ush1c was up-regulated when Ush2a was null. We also found that disruption of fibronectin assembly at the retinal basement membrane weakened cell adhesion inush2a−/− mutants. In summary, for the first time, we generated aush2a knockout zebrafish line with auditory disorder and retinal degeneration which mimicked the symptoms of patients, and revea...
Source: Human Genetics - Category: Genetics & Stem Cells Source Type: research