Journal Article

The Na/K-ATPase is obligatory for membrane anchorage of retinoschisin, the protein involved in the pathogenesis of X-linked juvenile retinoschisis

Ulrike Friedrich, Heidi Stöhr, Daniela Hilfinger, Thomas Loenhardt, Melitta Schachner, Thomas Langmann and Bernhard H.F. Weber

in Human Molecular Genetics

Volume 20, issue 6, pages 1132-1142
Published in print March 2011 | ISSN: 0964-6906
Published online December 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq557
The Na/K-ATPase is obligatory for membrane anchorage of retinoschisin, the protein involved in the pathogenesis of X-linked juvenile retinoschisis

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Mutations in the RS1 gene that encodes the discoidin domain containing retinoschisin cause X-linked juvenile retinoschisis (XLRS), a common macular degeneration in males. Disorganization of retinal layers and electroretinogram abnormalities are hallmarks of the disease and are also found in mice deficient for the orthologous murine protein, indicating that retinoschisin is important for the maintenance of retinal cell integrity. Upon secretion, retinoschisin associates with plasma membranes of photoreceptor and bipolar cells, although the components by which the protein is linked to membranes in vivo are still unclear. Here, we show that retinoschisin fails to bind to phospholipids or unilamellar lipid vesicles. A recent proteomic approach identified the Na/K-ATPase subunits ATP1A3 and ATP1B2 as binding partners of retinoschisin. We analyzed mice deficient for retinoschisin (Rs1h−/Y) and ATP1B2 (Atp1b2−/−) to characterize the role of Na/K-ATPase interaction in the organization of retinoschisin on cellular membranes. We demonstrate that both the Na/K-ATPase and retinoschisin are significantly reduced in Atp1b2−/− retinas, suggesting that retinoschisin membrane association is severely impaired in the absence of ATP1A3 and ATP1B2 subunits. Conversely, the presence of ATP1A3 and ATP1B2 are obligatory for binding of exogenously applied retinoschisin to crude membranes. Also, co-expression of ATP1A3 and ATP1B2 is required for retinoschisin binding to intact Hek293 cells. Taken together, our data support a predominant role of Na/K-ATPase in anchoring retinoschisin to retinal cell surfaces. Furthermore, altered localization of ATP1A3 and ATP1B2 is a notable consequence of retinoschisin deficiency and thus may be an important downstream aspect of cellular pathology in XLRS.

Journal Article.  6817 words.  Illustrated.

Subjects: Genetics and Genomics

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