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J. Biol. Chem., Vol. 278, Issue 30, 28139-28146, July 25, 2003

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Defective Discoidin Domain Structure, Subunit Assembly, and Endoplasmic Reticulum Processing of Retinoschisin are Primary Mechanisms Responsible for X-linked Retinoschisis^*

Winco W. H. Wu   and Robert S. Molday  ¶ ||

From the Department of Biochemistry and Molecular Biology and the ^¶Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, V6T 1Z3 Canada

Retinoschisin is a 24-kDa discoidin domain-containing protein that is secreted from photoreceptor and bipolar cells as a large disulfide-linked multisubunit complex. It functions as a cell adhesion protein to maintain the cellular organization and synaptic structure of the retina. Over 125 different mutations in the RS1 gene are associated with X-linked juvenile retinoschisis, the most common form of early onset macular degeneration in males. To identify molecular determinants important for retinoschisin structure and function and elucidate molecular and cellular mechanisms responsible for X-linked juvenile retinoschisis, we have analyzed the expression, protein folding, disulfide-linked subunit assembly, intracellular localization, and secretion of wild-type retinoschisin, 15 Cys-to-Ser variants and 12 disease-linked mutants. Our studies, together with molecular modeling of the discoidin domain, identify Cys residues involved in intramolecular and intermolecular disulfide bonds essential for protein folding and subunit assembly. We show that misfolding of the discoidin domain, defective disulfide-linked subunit assembly, and inability of retinoschisin to insert into the endoplasmic reticulum membrane as part of the protein secretion process are three primary mechanisms responsible for the loss in the function of retinoschisin as a cell adhesion protein and the pathogenesis of X-linked juvenile retinoschisis.

Received for publication, March 10, 2003 , and in revised form, April 15, 2003.

^* This work was supported by Grant EY 02422 from the National Institutes of Health and Grant MT 5822 from Canadian Institutes of Health Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by scholarships from the Natural Sciences and Engineering Research Council (Canada), and the Michael Smith Foundation for Health Research.

^|| Canada Research Chair in Vision and Macular Degeneration. To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, 2146 Health Sciences Mall, University of British Columbia, Vancouver, BC, Canada V6T 1Z3. Tel.: 604-822-6173; Fax: 604-822-5227; Email: molday{at}interchange.ubc.ca.

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