Centre for Molecular Medicine and Innovative Therapeutics, Health Futures Institute, Murdoch University, Murdoch, Western Australia, Australia.
Lions Eye Institute, Nedlands, Western Australia, Australia.
Asia Pac J Ophthalmol (Phila). 2022;11(4):369-379. doi: 10.1097/APO.0000000000000546. Epub 2022 Aug 17.
Usher syndrome (USH) is the most common form of deaf-blindness, with an estimated prevalence of 4.4 to 16.6 per 100,000 people worldwide. The most common form of USH is type IIA (USH2A), which is caused by homozygous or compound heterozygous mutations in the USH2A gene and accounts for around half of all USH cases. USH2A patients show moderate to severe hearing loss from birth, with diagnosis of retinitis pigmentosa in the second decade of life and variable vestibular involvement. Although hearing aids or cochlear implants can provide some mitigation of hearing deficits, there are currently no treatments aimed at preventing or restoring vision loss in USH2A patients. In this review, we first provide an overview of the molecular biology of the USH2A gene and its protein isoforms, which include a transmembrane protein (TM usherin) and an extracellular protein (EC usherin). The role of these proteins in the inner ear and retina and their impact on the pathogenesis of USH2A is discussed. We review animal cell-derived and patient cell-derived models currently used in USH2A research and conclude with an overview of potential treatment strategies currently in preclinical development and clinical trials.
先天性耳聋-色素性视网膜炎（USH）是最常见的聋盲综合征之一，估计全球每 10 万人中有 4.4 至 16.6 人患病。最常见的 USH 类型是 IIA 型（USH2A），它是由 USH2A 基因突变引起的纯合子或复合杂合子突变，约占所有 USH 病例的一半。USH2A 患者出生时即有中度至重度听力损失，在人生的第二个十年中被诊断为色素性视网膜炎，并伴有不同程度的前庭功能障碍。尽管助听器或人工耳蜗可以部分减轻听力缺陷，但目前尚无针对 USH2A 患者预防或恢复视力丧失的治疗方法。在这篇综述中，我们首先概述了 USH2A 基因及其蛋白异构体的分子生物学，包括一种跨膜蛋白（TM usherin）和一种细胞外蛋白（EC usherin）。讨论了这些蛋白在内耳和视网膜中的作用及其对 USH2A 发病机制的影响。我们回顾了目前用于 USH2A 研究的动物细胞衍生和患者细胞衍生模型，并概述了目前处于临床前开发和临床试验阶段的潜在治疗策略。
