Ploessl, Karolina and Schmid, Verena and Straub, Kristina and Schmid, Carina and Ammon, Mirjam and Merkl, Rainer and Weber, Bernhard H. F. and Friedrich, Ulrike (2018) Pathomechanism of mutated and secreted retinoschisin in X-linked juvenile retinoschisis. EXPERIMENTAL EYE RESEARCH, 177. pp. 23-34. ISSN 0014-4835, 1096-0007
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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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACTIVATED PROTEIN-KINASE; NA/K-ATPASE; GENE; RS1; EXPRESSION; RHODOPSIN; PHOTORECEPTOR; MUTATIONS; ADHESION; MUTANTS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 Oct 2019 08:49 |
| Last Modified: | 04 Oct 2019 08:49 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13416 |
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