Stemerdink M, García-Bohórquez B, Schellens R, Garcia-Garcia G, Van Wijk E, Millan J M
Department of Otorhinolaryngology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.
Grupo de Investigación en Biomedicina Molecular, Celular y Genómica Health Research Institute La Fe, Valencia, Spain.
Hum Genet. 2022 Apr;141(3-4):737-758. doi: 10.1007/s00439-021-02324-w. Epub 2021 Jul 30.
Usher syndrome (USH) is a rare, autosomal recessively inherited disorder resulting in a combination of sensorineural hearing loss and a progressive loss of vision resulting from retinitis pigmentosa (RP), occasionally accompanied by an altered vestibular function. More and more evidence is building up indicating that also sleep deprivation, olfactory dysfunction, deficits in tactile perception and reduced sperm motility are part of the disease etiology. USH can be clinically classified into three different types, of which Usher syndrome type 2 (USH2) is the most prevalent. In this review, we, therefore, assess the genetic and clinical aspects, available models and therapeutic developments for USH2. Mutations in USH2A, ADGRV1 and WHRN have been described to be responsible for USH2, with USH2A being the most frequently mutated USH-associated gene, explaining 50% of all cases. The proteins encoded by the USH2 genes together function in a dynamic protein complex that, among others, is found at the photoreceptor periciliary membrane and at the base of the hair bundles of inner ear hair cells. To unravel the pathogenic mechanisms underlying USH2, patient-derived cellular models and animal models including mouse, zebrafish and drosophila, have been generated that all in part mimic the USH phenotype. Multiple cellular and genetic therapeutic approaches are currently under development for USH2, mainly focused on preserving or partially restoring the visual function of which one is already in the clinical phase. These developments are opening a new gate towards a possible treatment for USH2 patients.
尤塞综合征（USH）是一种罕见的常染色体隐性遗传疾病，会导致感音神经性听力损失，并因色素性视网膜炎（RP）导致视力逐渐丧失，偶尔还伴有前庭功能改变。越来越多的证据表明，睡眠剥夺、嗅觉功能障碍、触觉感知缺陷和精子活力降低也是该疾病病因的一部分。USH在临床上可分为三种不同类型，其中尤塞综合征2型（USH2）最为常见。因此，在本综述中，我们评估了USH2的遗传和临床方面、现有模型以及治疗进展。已发现USH2A、ADGRV1和WHRN中的突变与USH2有关，其中USH2A是USH相关基因中最常发生突变的基因，占所有病例的50%。USH2基因编码的蛋白质共同在一个动态蛋白质复合物中发挥作用，该复合物尤其存在于光感受器纤毛周膜和内耳毛细胞的毛束基部。为了阐明USH2的致病机制，已经建立了包括小鼠、斑马鱼和果蝇在内的患者来源的细胞模型和动物模型，这些模型都部分模拟了USH表型。目前正在为USH2开发多种细胞和基因治疗方法，主要集中在保留或部分恢复视觉功能，其中一种已经进入临床阶段。这些进展为USH2患者的可能治疗打开了一扇新的大门。
