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      Characterization of novel RS1 exonic deletions in juvenile X-linked retinoschisis

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          X-linked juvenile retinoschisis (XLRS) is a vitreoretinal dystrophy characterized by schisis (splitting) of the inner layers of the neuroretina. Mutations within the retinoschisis ( RS1) gene are responsible for this disease. The mutation spectrum consists of amino acid substitutions, splice site variations, small indels, and larger genomic deletions. Clinically, genomic deletions are rarely reported. Here, we characterize two novel full exonic deletions: one encompassing exon 1 and the other spanning exons 4–5 of the RS1 gene. We also report the clinical findings in these patients with XLRS with two different exonic deletions.


          Unrelated XLRS men and boys and their mothers (if available) were enrolled for molecular genetics evaluation. The patients also underwent ophthalmologic examination and in some cases electroretinogram (ERG) recording. All the exons and the flanking intronic regions of the RS1 gene were analyzed with direct sequencing. Two patients with exonic deletions were further evaluated with array comparative genomic hybridization to define the scope of the genomic aberrations. After the deleted genomic region was identified, primer walking followed by direct sequencing was used to determine the exact breakpoints.


          Two novel exonic deletions of the RS1 gene were identified: one including exon 1 and the other spanning exons 4 and 5. The exon 1 deletion extends from the 5′ region of the RS1 gene (including the promoter) through intron 1 (c.(−35)-1723_c.51+2664del4472). The exon 4–5 deletion spans introns 3 to intron 5 (c.185–1020_c.522+1844del5764).


          Here we report two novel exonic deletions within the RS1 gene locus. We have also described the clinical presentations and hypothesized the genomic mechanisms underlying these schisis phenotypes.

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          Most cited references 19

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          A perfect message: RNA surveillance and nonsense-mediated decay.

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            X linked retinoschisis.

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              Defective discoidin domain structure, subunit assembly, and endoplasmic reticulum processing of retinoschisin are primary mechanisms responsible for X-linked retinoschisis.

               Bo Wu,  Robert Molday (2003)
              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.

                Author and article information

                Mol Vis
                Mol. Vis
                Molecular Vision
                Molecular Vision
                07 November 2013
                : 19
                : 2209-2216
                [1 ]Ophthalmic Genetics and Visual Function Branch, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, MD
                [2 ]Department of Pediatrics, The University of Oklahoma, Oklahoma City, OK
                [3 ]Office of the Director, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, MD
                Author notes
                Correspondence to: Xinjing Wang, Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, 10D43, 10 Center Drive, Bethesda, MD 20892; Phone: (301) 435 4568; FAX: (301) 451 5499; wangx6@ 123456nei.nih.gov
                Dr. Lee is now at Department of Pathology, Korea University, Seoul, Republic of Korea. Dr. Smaoui is now at GeneDx, Rockville, MD.
                221 2013MOLVIS0260
                Copyright © 2013 Molecular Vision.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited, used for non-commercial purposes, and is not altered or transformed.

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