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      R213W mutation in the retinoschisis 1 gene causes X-linked juvenile retinoschisis in a large Chinese family

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          We identified a large Chinese family with X-linked juvenile retinoschisis. The purpose of this study was to report the clinical findings of the family and to identify the genetic mutation by screening the retinoschisis 1 ( RS1) gene.


          Family history was collected and all family members underwent routine ophthalmic examination. Venous blood was collected from family members and genomic DNA was extracted. The exons of RS1 were screened by PCR followed by direct sequencing and/or restriction enzyme digestion.


          The pedigree of interest was a four-generation family with 52 family members, including seven affected individuals. The proband was a 5-year-old boy showing highly elevated bullous retinoschisis with moderate vitreous hemorrhage in both eyes. Vitrectomy was performed in the left eye of the proband. Five affected males showed large peripheral retinoschisis in both eyes, either involving the macula or combined with foveal stellate cystic change. One of the affected family members showed only a foveal stellate cystic change in both eyes without periphery retinoschisis. Visual acuity of affected individuals ranged from hand motion to 0.4. The R213W mutation in exon 6 of RS1 was identified in all affected individuals, predicting an amino acid substitution of arginine to tryptophan at codon 213.


          Our data show that the R213W mutation in RS1 causes various severities of retinoschisis in a large Chinese family, providing further evidence for X-linked juvenile retinoschisis phenotypic variability.

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          X linked retinoschisis.

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            Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis. The Retinoschisis Consortium.

            X-linked retinoschisis (XLRS) is the most common cause of juvenile macular degeneration in males, resulting in vision loss early in life. The gene involved in XLRS was identified recently. It encodes a protein with a disoidin domain, suggested to be involved in cell-cell interactions. We have screened the gene for mutations in 234 familial and sporadic retinoschisis cases and identified 82 different mutations in 214 (91%). Thirty one mutations were found more than once, i.e. 2-10 times, with the exception of the 214G-->A mutation which was found in 34 apparently unrelated cases. The origin of the patients, the linkage data and the site of the mutations (mainly CG dinucleotides) indicate that most recurrent mutations had independent origins and thus suggest the existence of a significant new mutation rate in XLRS1. The mutations identified cover the entire spectrum, from small intra-genic deletions (7%), to nonsense (6%), missense (75%), small frameshifting insertions/deletions (6%) and splice site mutations (6%). Since, regardless of the mutation type, no females with a typical RS phenotype were identified, RS seems to be caused by loss-of-function mutations only. Mutations occurred non-randomly, with hotspots at several CG dinucleotides and a C6stretch. Exons 1-3 contained few, mainly translation-truncating mutations, arguing against an important functional role for this segment of the protein. Exons 4-6, encoding the discoidin domain, contained most, mainly missense mutations. An alignment of 32 discoidin domain proteins was constructed to reveal the consensus sequence and to deduce the functional importance of the missense mutations identified. The mutation analysis revealed a high preponderance of mutations involving or creating cysteine residues, pointing to sites important for the tertiary folding and/or protein function, and highlights several amino acids which may be involved in XLRS1-specific protein-protein interactions. Despite the enormous mutation heterogeneity, patients have relatively uniform clinical manifestations although with great intra-familial variation in age at onset and progression.
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              Expression of X-linked retinoschisis protein RS1 in photoreceptor and bipolar cells.

              To examine the biochemical properties, cell expression, and localization of RS1, the product of the gene responsible for X-linked juvenile retinoschisis. Rs1h mRNA expression was measured from the eyes of wild-type and rd/rd mice by Northern blot analysis and reverse transcription-polymerase chain reaction (RT-PCR). Specific antibodies raised against the N terminus of RS1 were used as probes to examine the properties and distribution of RS1 in retina, retinal cell cultures, and transfected COS-1 cells by Western blot analysis and immunofluorescence microscopy. Rs1h mRNA expression was detected in the retina of postnatal day (P)11 and adult CD1 mice, but not homozygous rd/rd mice by Northern blot analysis. However, Rs1h expression was detected in rd/rd mice by RT-PCR. RS1 migrated as a single 24-kDa polypeptide under disulfide-reducing conditions and a larger complex (>95 kDa) under nonreducing conditions in the membrane fraction of retinal tissue homogenates and transfected COS-1 cells. RS1 antibodies specifically stained rod and cone photoreceptors and most bipolar cells, but not Müller cells, ganglion cells, or the inner limiting membrane of adult and developing retina as revealed in double-labeling studies. RS1 antibodies also labeled retinal bipolar cells of photoreceptorless mice and retinal bipolar cells grown in cell culture. RS1 is expressed and assembled in photoreceptors of the outer retina and bipolar cells of the inner retina as a disulfide-linked oligomeric protein complex. The secreted complex associates with the surface of these cells, where it may function as a cell adhesion protein to maintain the integrity of the central and peripheral retina.

                Author and article information

                Mol Vis
                Molecular Vision
                Molecular Vision
                12 August 2010
                : 16
                : 1593-1600
                [1 ]Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, China
                [2 ]Sekwa Eye Hospital, Beijing, China
                Author notes
                Correspondence to: Ningpu Liu, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, No. 1 Dong Jiao Min Xiang, Dongcheng District, Beijing 100730, China; Phone: +86 10 58266012; FAX: +86 10 62033293; email: nliu001@ 123456gmail.com
                171 2010MOLVIs0112
                Copyright © 2010 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.

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