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BH F Weber, H Schrewe, LL Molday, A Gehrig, MW Seeliger, C Friedburg, E Tamm, RS Molday; Inactivation of the Murine X-linked Juvenile Retinoschisis Gene, Rs1h, Suggests a Role of Retinoschisin in Retinal Cell Layer Organization and Synaptic Structure . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3664.
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Purpose: Deleterious mutations in RS1 encoding retinoschisin are associated with X-linked juvenile retinoschsis (RS), a common form of macular degeneration in males. Retinoschisin is a retina-specific polypeptide of 24 kDa that is secreted as a disulfide-linked oligomeric protein complex from both the rod and cone photoreceptors and the bipolar cells. To gain further insight into the function of retinoschisin and its role in the cellular pathology of RS, we have generated knock-out mice deficient in Rs1h, the murine ortholog of RS1. Methods: The Rs1h gene was targeted in exon 3 with a bpA-PGK-neor-bpA cassette. Hemizygous male mice were assessed by scanning-laser ophthalmoscopy, electroretinography (ERG) under scotopic and photopic conditions, by histology, transmission electron microscopy and immunofluorescence labeling using a variety of retinal antibodies. Results: ERG studies in Rs1h-/Y male mice demonstrate characteristic anomalies consistent with the human condition, while in the absence of a macula in the mouse in vivo imaging revealed an even distribution of cyst-like structures. In histologic sections, there is marked splitting of the inner nuclear layer, overall disorganization of the retinal cell layers with irregular displacement of cells, and later degeneration of the photoreceptors which appears more pronounced in cones. In the Rs1h-/Y retina we observed disturbed vectorial transport of PSD-95 to the outer and inner plexiform layers, where Rs1h is ordinarily present in high amounts. PSD-95 is a synapse-associated protein and plays a crucial role in the targeting and clustering of ligand- and/or voltage-gated ion channels at synaptic junctions. Conclusion: Our findings in the knock-out mouse model suggest that, via its discoidin domain, retinoschisin is directly or indirectly involved in the organization of the retinal cell layers and may play an important role in the assembly and stabilization of the retinal synapse.
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