Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL, USA.
Adv Exp Med Biol. 2018;1074:61-66. doi: 10.1007/978-3-319-75402-4_8.
The pathogenic mutation S163R in C1QTNF5 causes a disorder known as autosomal dominant late-onset retinal degeneration (L-ORD), characterized by the presence of thick extracellular sub-RPE deposits, similar histopathologically to those found in AMD patients. We have previously shown that the S163R C1QTNF5 mutant forms globular aggregates within the RPE in vivo following its AAV-mediated expression in the RPE and exhibits a reversely polarized distribution, being routed toward the basal rather than apical RPE. We show here that when both wild-type and mutant S163R C1QTNF5 are simultaneously delivered subretinally to mouse RPE cells, the mutant impairs the wild-type protein secretion from the RPE, and both proteins are dispersed toward the basal and lateral RPE membrane. This result has mechanistic and therapeutic implications for L-ORD disorder.
C1QTNF5 中的致病突变 S163R 导致一种称为常染色体显性晚发性视网膜变性（L-ORD）的疾病，其特征是存在厚的细胞外 RPE 下沉积物，在组织病理学上与 AMD 患者中发现的沉积物相似。我们之前已经表明，在 RPE 中经 AAV 介导表达后，S163R C1QTNF5 突变体在体内形成球状聚集物，并表现出反向极化分布，被引导朝向基底而不是顶侧 RPE。我们在这里表明，当野生型和突变型 S163R C1QTNF5 同时被递送至小鼠 RPE 细胞下时，突变型会损害 RPE 中野生型蛋白的分泌，并且两种蛋白都分散到基底和侧 RPE 膜。这一结果对 L-ORD 疾病具有机制和治疗意义。
