Usher syndrome (USH) is the leading cause of combined deafness and blindness, with USH2A being the most prevalent form. The mechanisms responsible for this debilitating sensory impairment remain unclear. This study focuses on characterizing the auditory phenotype in a mouse model expressing the c.2290delG mutation in usherin equivalent to human frameshift mutation c.2299delG. Previously we described how this model reproduces patient’s retinal phenotypes. Here, we present the cochlear phenotype, showing that the mutant usherin, is expressed during early postnatal stages. The c.2290delG mutation results in a truncated protein that is mislocalized within the cell body of the hair cells. The knock-in model also exhibits congenital hearing loss that remains consistent throughout the animal’s lifespan. Structurally, the stereocilia bundles, particularly in regions associated with functional hearing loss, are disorganized. Our findings shed light on the role of usherin in maintaining structural support, specifically in longer inner hair cell stereocilia, during development, which is crucial for proper bundle organization and hair cell function. Overall, we present a genetic mouse model with cochlear defects associated with the c.2290delG mutation, providing insights into the etiology of hearing loss and offering potential avenues for the development of effective therapeutic treatments for USH2A patients.

亚瑟综合征 (USH) 是导致耳聋和失明的主要原因，其中 USH2A 是最常见的形式。造成这种使人衰弱的感觉障碍的机制仍不清楚。本研究的重点是表征小鼠模型中的听觉表型，该小鼠模型表达 usherin 中的 c.2290delG 突变，相当于人类移码突变 c.2299delG。之前我们描述了该模型如何再现患者的视网膜表型。在这里，我们展示了耳蜗表型，表明突变的 usherin 在出生后早期表达。 c.2290delG 突变导致截短的蛋白质错误定位在毛细胞的细胞体内。敲入模型还表现出先天性听力损失，这种损失在动物的整个生命周期中都保持一致。在结构上，静纤毛束，特别是与功能性听力损失相关的区域，是杂乱无章的。我们的研究结果揭示了引导蛋白在发育过程中维持结构支撑的作用，特别是在较长的内毛细胞静纤毛中，这对于正确的束组织和毛细胞功能至关重要。总体而言，我们提出了一种具有与 c.2290delG 突变相关的耳蜗缺陷的遗传小鼠模型，为了解听力损失的病因提供了见解，并为开发针对 USH2A 患者的有效治疗方法提供了潜在途径。