Retinoschisin (RS1) is a secreted protein that is essential for maintaining integrity of the retina. Numerous mutations in RS1 cause X-linked retinoschisis (XLRS), a progressive degeneration of the retina that leads to vision loss in young males. A key manifestation of XLRS is the formation of cavities (cysts) in the retina and separation of the layers (schisis), disrupting synaptic transmission. There are currently no approved treatments for patients with XLRS. Strategies using adeno-associated viral (AAV) vectors to deliver functional copies of RS1 as a form of gene augmentation therapy, are under clinical evaluation. To improve therapeutic strategies for treating XLRS, it is critical to better understand the secretion of RS1 and its molecular function. Immunofluorescence and immunoelectron microscopy show that RS1 is located on the surfaces of the photoreceptor inner segments and bipolar cells. Sequence homology indicates a discoidin domain fold, similar to many other proteins with demonstrated adhesion functions. Recent structural studies revealed the tertiary structure of RS1 as two back-to-back octameric rings, each cross-linked by disulfides. The observation of higher order structures in vitro suggests the formation of an adhesive matrix spanning the distance between cells (∼100 nm). Several studies indicated that RS1 readily binds to other proteins such as the sodium-potassium ATPase (NaK-ATPase) and extracellular matrix proteins. Alternatively, RS1 may influence fluid regulation via interaction with membrane proteins such as the NaK-ATPase, largely inferred from the use of carbonic anhydrase inhibitors to shrink the typical intra-retinal cysts in XLRS. We discuss these models in light of RS1 structure and address the difficulty in understanding the function of RS1.

视网膜裂素 (RS1) 是一种分泌蛋白，对于维持视网膜的完整性至关重要。RS1 的大量突变会导致 X 连锁视网膜劈裂 (XLRS)，这是一种视网膜进行性退化，会导致年轻男性视力丧失。XLRS 的一个关键表现是在视网膜中形成空洞（囊肿）和各层分离（分裂），从而扰乱突触传递。目前尚无批准用于 XLRS 患者的治疗方法。使用腺相关病毒 (AAV) 载体传递 RS1 功能副本作为基因增强疗法的策略正在接受临床评估。为了改进 XLRS 的治疗策略，更好地了解 RS1 的分泌及其分子功能至关重要。免疫荧光和免疫电镜显示RS1位于光感受器内节和双极细胞的表面。序列同源性表明盘状蛋白结构域折叠，类似于许多其他具有粘附功能的蛋白质。最近的结构研究揭示了RS1的三级结构为两个背对背的八聚环，每个环由二硫键交联。对体外高级结构的观察表明，形成了跨越细胞之间距离（​​~100 nm）的粘附基质。多项研究表明，RS1 很容易与其他蛋白质结合，例如钠钾 ATP 酶 (NaK-ATP 酶) 和细胞外基质蛋白。另外，RS1 可能通过与膜蛋白（例如 NaK-ATP 酶）相互作用来影响液体调节，很大程度上是由于使用碳酸酐酶抑制剂来缩小 XLRS 中典型的视网膜内囊肿。我们根据 RS1 结构讨论这些模型，并解决理解 RS1 功能的困难。