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The retinoschisin protein is encoded on the short arm of the X-chromosome by RS1, is expressed abundantly in photoreceptor inner segments and in bipolar cells, and is secreted as an octamer that maintains the structural integrity of the retina. Mutations in RS1 lead to X-linked retinoschisis (XLRS), a disease characterized by the formation of cystic spaces between boys' retinal layers that frequently present in ophthalmoscopy as a "spoke-wheel" pattern on their maculae and by progressively worsening visual acuity (VA). There is no proven therapy for XLRS, but there is mixed evidence that carbonic anhydrase inhibitors (CAIs) produce multiple beneficial effects, including improved VA and decreased volume of cystic spaces. Consequently, linear mixed-effects (LME) models were used to evaluate the effects of CAI therapy on VA and central retinal thickness (CRT, a proxy for cystic cavity volume) in a review of 19 patients' records. The mechanism of action of action of CAIs is unclear but, given that misplaced retinoschisin might accumulate in the photoreceptors, it is possible-perhaps even likely-that CAIs act to benefit the function of photoreceptors and the neighboring retinal pigment epithelium by acidification of the extracellular milieu; patients on CAIs have among the most robust photoreceptor responses. Therefore, a small subset of five subjects were recruited for imaging on a custom multimodal adaptive optics retinal imager for inspection of their parafoveal cone photoreceptors. Those cones that were visible, which numbered far fewer than in controls, were enlarged, consistent with the retinoschisin accumulation hypothesis. Results of the LME modeling found that there is an initial benefit to both VA and CRT in CAI therapy, but these wane, in both cases, after roughly two years. That said, even a short beneficial effect of CAIs on the volume of the cystic spaces may give CAI therapy an important role as pretreatment before (or immediately following) administration of gene therapy., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Mutations in the RS1 gene encoding retinoschisin cause X-linked juvenile retinoschisis (XLRS), a hereditary retinal dystrophy in males. While most of the XLRS associated mutations strongly interfere with cellular secretion, this is not true for mutants RS1-F108C, -R141G, -R141H, -R182C, -H207Q and -R209H. Native retinoschisin builds double-octamers and binds to retinal membranes, interacting with the retinal Na/K-ATPase. Functionally, it regulates MAP kinase signaling and Na/K-ATPase localization, and hampers photoreceptor degeneration. In this study, we investigated the capacity of the retinoschisin mutants still secreted extracellularly to fulfil these tasks. We addressed secretion and oligomerization of the heterologously expressed mutants as well as their binding to recombinant retinal Na/K-ATPases and murine retinoschisin-deficient (Rs1h -/Y ) retinal and non-retinal explants. This has refined the categorization of secreted retinoschisin mutants: (i) no octamerization, unspecific membrane binding (RS1-F108C and -R182C), (ii) double-octamerization but no membrane binding (RS1-R141H), and (iii) double-octamerization and unspecific membrane binding (RS1-R141G, -H207Q, and -R209H). Notably, selected mutants of all categories (RS1-F108C, -R141H, and -R209H) failed to regulate retinal MAP kinase signaling and Na/K-ATPase localization in Rs1h -/Y retinal explants, and could not attenuate photoreceptor degeneration. Bioinformatic modeling of the secreted mutants depicted prominent alterations in the spatial and temporal conformation of a substructure called "spike 3" and its vicinity, implying a crucial role of this substructure for binding capacity and specificity. Taken together, our data point to a pathomechanism for secreted retinoschisin mutants, specifically to disturbances of the retinoschisin interface accompanied by unphysiological membrane interactions and impaired regulatory functions., (Copyright © 2018 Elsevier Ltd. All rights reserved.)