PDF(Pubmed)
Abstract：
The BEST1 gene encodes bestrophin-1, a homopentameric ion channel expressed in the retinal pigment epithelium (RPE), where it localizes to the basolateral plasma membrane. Pathogenic variants in this gene can cause different autosomal dominant and recessive inherited retinal diseases (IRDs), collectively named \"bestrophinopathies.\" These disorders share a number of clinical and molecular features that make them an appealing target for gene therapy. Clinically, bestrophinopathies are often slowly progressive with a wide window of opportunity, and the presence of subretinal material (vitelliform deposits and/or fluid) as a hallmark of these conditions provides an easily quantifiable endpoint in view of future clinical trials. From a molecular standpoint, most BEST1 pathogenic variants have been shown to cause either loss of function (LOF) of the protein or a dominant-negative (DN) effect, with a smaller subset causing a toxic gain of function (GOF). Both LOF and DN mutations may be amenable to gene augmentation alone. On the other hand, individuals harboring GOF variants would require a combination of gene silencing and gene augmentation, which has been shown to be effective in RPE cells derived from patients with Best disease. In this article, we review the current knowledge of BEST1-related IRDs and we discuss how their molecular and clinical features are being used to design novel and promising therapeutic strategies.
摘要：
BEST1基因编码bestrophin-1，一种在视网膜色素上皮（RPE）中表达的同五聚体离子通道，它位于基底外侧质膜。该基因的致病变异可引起不同的常染色体显性和隐性遗传性视网膜疾病（IRD），统称为“bestrophinopathies”。“这些疾病具有许多临床和分子特征，使其成为基因治疗的有吸引力的靶标。临床上,蛇床子病通常是缓慢发展的，机会很大，和视网膜下物质（卵黄样沉积物和/或液体）的存在作为这些条件的标志提供了一个容易量化的终点，考虑到未来的临床试验。从分子的角度来看，大多数BEST1致病变体已被证明会导致蛋白质功能丧失（LOF）或显性阴性（DN）效应，较小的子集引起毒性功能增益(GOF)。LOF和DN突变均可单独进行基因扩增。另一方面,携带GOF变体的个体需要基因沉默和基因增强的组合，已被证明对来自Best疾病患者的RPE细胞有效。在这篇文章中,我们回顾了BEST1相关IRD的最新知识,并讨论了它们的分子和临床特征如何被用于设计新颖且有前景的治疗策略.
