Novel mutations in XLRS1 causing retinoschisis, including first evidence of putative leader sequence change

Hiriyanna, K. T.; Bingham, Eve L.; Yashar, Beverly M.; Ayyagari, Radha; Fishman, Gerald A.; Small, Kent W.; Weinberg, David V.; Weleber, Richard G.; Lewis, Richard A.; Andréasson, Sten; Richards, Julia E.; Sieving, Paul A.

doi:10.1002/(sici)1098-1004(199911)14:5<423::aid-humu8>3.0.co;2-d

Cited by 41 publications

(28 citation statements)

References 22 publications

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“…One group comprises mutations in the hydrophobic leader sequence (4). As shown here, the L13P mutation results in a marked decrease in protein expression and irregular localization to the cytoplasmic compartment of the cell.…”

Section: Fig 3 Expression and Characterization Of Double Cys Mutantsmentioning

confidence: 99%

“…It is characterized by a mild to severe decrease in visual acuity, radial streaks extending from the central retina due to a splitting of the inner retina, progressive macular atrophy, and reduction in the electroretinogram b-wave (2)(3)(4)(5). Lesions in the peripheral retina associated with impairment in peripheral vision are observed in half the cases.…”

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confidence: 99%

“…Most missense mutations are in the discoidin domain of retinoschisin, with over 25% involving the loss or gain of a Cys residue. Disease-causing missense mutations are also found in regions flanking the discoidin domain as well as within the leader sequence (4,19).…”

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confidence: 99%

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

Molday

2003

Journal of Biological Chemistry

101

136

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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.X-linked juvenile retinoschisis (XLRS) 1 is the most common form of early onset macular degeneration in males (1, 2). It is characterized by a mild to severe decrease in visual acuity, radial streaks extending from the central retina due to a splitting of the inner retina, progressive macular atrophy, and reduction in the electroretinogram b-wave (2-5). Lesions in the peripheral retina associated with impairment in peripheral vision are observed in half the cases. During the course of the disease, complications can arise, which include retinal detachment, vitreal hemorrhaging, and neovascular glaucoma leading to a poor outcome.The RS1 gene responsible for XLRS was identified by positional cloning and found to encode a 24-kDa protein called retinoschisin, or RS1 (6), that is secreted from photoreceptor and bipolar cells as a disulfide-linked oligomeric complex (7,8).The polypeptide consists of a leader sequence with a putative signal peptidase cleavage site and a discoidin domain spanning most of the protein (6). Discoidin domains, first identified in the discoidin I protein of Dictyostelium discoidium (9, 10), have now been found in many secreted and transmembrane proteins, including blood coagulation factors, tyrosine kinase receptors, and proteins involved in neural development (11-13). The function of the discoidin domain is not well understood, but in some proteins it has been implicated in cell adhesion and cell signaling through protein-protein, protein-carbohydrate, or protein-lipid interactions. Recently, the three-dimensional crystal structures of the C2 discoidin domain of blood coagulation Factors...

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Section: Fig 3 Expression and Characterization Of Double Cys Mutantsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Molday

2003

Journal of Biological Chemistry

101

136

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“…About 125 mutations in the XLRS-1 gene have been described so far, including point mutations as well as deletions of single or multiple nucleotides, leading to frame shifts or truncations (31,32). More than 80% of these mutations are located in the conserved discoidin repeat.…”

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confidence: 99%

Mapping of Epitopes in Discoidin Domain Receptor 1 Critical for Collagen Binding

Curat¹,

Eck²,

Dervillez³

et al. 2001

Journal of Biological Chemistry

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The binding and activation of the discoidin domain receptor 1 by collagen has led to the conclusion that proteins from the extracellular matrix can directly induce receptor tyrosine kinase-mediated signaling cascades. A region in the extracellular domain of DDR1 homologous to the Dictyostelium discoideum protein discoidin-I is also present in the secreted human protein RS1. Mutations in RS1 cause retinoschisis, a genetic disorder characterized by ablation of the retina. By introducing point mutations into the discoidin domain of DDR1 at positions homologous to the retinoschisis mutations, ligand binding epitopes in the discoidin domain of DDR1 were mapped. Surprisingly, some residues only affected receptor phosphorylation, whereas others influenced both collagen-binding and receptor activation. Furthermore, two truncated DDR1 variants, lacking either the discoidin domain or the stalk region between the discoidin and transmembrane domain, were generated. We showed that (i) the discoidin domain was necessary and sufficient for collagen binding, (ii) only the region between discoidin and transmembrane domain was glycosylated, and (iii) the entire extracellular domain was essential for transmembrane signaling. Using these results, we were able to predict key sites in the collagen-binding epitope of DDR1 and to suggest a potential mechanism of signaling.Discoidin domain receptors 1 and 2 (DDR1 and DDR2) 1 have been recognized as a distinct tyrosine kinase receptor subfamily because of structural and functional homologies. In their extracellular region, both receptors show a domain homologous to the Dictyostelium discoideum protein discoidin I. DDR1 and DDR2 are also functionally related by the observation that collagen acts as cognate ligand for both receptors. Whereas DDR1 activation is achieved by all collagens so far tested (types I-VI and VIII), DDR2 is only activated by fibrillar collagens, in particular by collagen type I and type III. In contrast to most other tyrosine kinase receptors, activation of DDRs can take several hours (1, 2).The cDNA coding for human DDR1 has been cloned from several tissues or carcinoma cells (3-7). Gene orthologs to human DDR1 have been identified in mice, rats, and Caenorhabditis elegans (8 -10). Expression of human DDR1 is predominantly seen in epithelial cells, particularly from kidney, lung, gastrointestinal tract, and brain, but also in corneal and dermal fibroblasts (7, 9, 11-13). DDR1 seems to be also involved in the differentiation of cerebellar granular neurons (14). Upregulated DDR1 expression has been reported from breast, ovarian, esophagus and brain tumors (5,(15)(16)(17)(18)(19). Human DDR1 is located on chromosome 6p21.3 in close proximity to HLA genes, which belong to the telomeric region (class I) of the major histocompatibility complex (20). The juxtamembrane regions in DDR1 and DDR2 are much longer than in other receptor tyrosine kinases (176 and 147 amino acids, respectively). Furthermore, the extracellular domain of DDR1 is shed by an unidentified protease, res...

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“…X-linked retinoschisis disease was reported in several families with missense mutations in signal sequence of RS1 gene, a 38T→ C which changes an amino acid residue Leu13Pro and 35T→ A which changes an amino acid residue Leu12H is in the signal sequence (Fig-1C) [23,24]. Replacing the hydrophobic Leu by the highly hydrophilic and neutral/positively charged His in the Leu12His mutant caused intracellular retention and failure to secrete the mutant protein [24].…”

Section: Missense Mutations In Signal Peptide and Xlrsmentioning

confidence: 99%

Identification and characterization of two mature isoforms of retinoschisin in murine retina

Vijayasarathy

Gawinowicz

Zeng

et al. 2006

Biochemical and Biophysical Research Communications

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Retinoschisin (RS) is a 24 kDa secreted protein expressed in retina and is required for the structural and functional integrity of the retina. RS has been predicted to serve as an adhesive protein but the precise molecular mechanism by which it functions in retina is not yet known. During investigations on structural and functional aspects of RS in murine retina using proteomic tools, we identified two isoforms of RS that differed in mass by 200 Da with no apparent change in charge. Mass spectra and amino acid sequence analysis of the tryptic peptides revealed that these isoforms differed by two amino acids at the N-terminus which suggested processing of RS signal sequence at two cleavage sites by signal peptidase as the basic mechanism underlying the occurrence of two mature RS isoforms in retina. Bioinformatic analysis identified two potential cleavage sites (between amino acids 21-22 and 23-24) in RS signal sequence. The flexibility of the signal peptidase to cleave at two sites is correlated to the amino acid composition of the RS signal sequence. This finding represents a rare example of a naturally occurring signal sequence cleavage at more than one site in vivo. KeywordsRetina; Retinoschisin; Post-Translational Modifications; Isoforms; Signal Sequence; Signal peptidase; Processing; X-linked retinoschisis; Missense mutations Retinoschisin (RS) is a 24 kDa secreted protein expressed in retina and pineal * and is required for the structural and functional integrity of the retina [1]. Based on its conserved discoidin domain sequence, RS is predicted to serve as an adhesion protein in maintaining the organization of the retina [1] but a precise molecular description of RS function is not yet known. Mutations in the RS1 gene that encodes the RS protein cause monogenic X-linked retinoschisis (XLRS) in young males [2][3][4]. Retinoschisis is a form of juvenile macular Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errorsmaybe discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. * Takada et. al.(2006 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript degeneration in which schisis or splitting within the nuclear and plexiform layers of the retina [5] leads to progressive loss of vision beginning at a young age [6]. Gene therapy is being considered as a therapeutic approach to treat XLRS disease which otherwise has no known cure [7].RS is synthesized in retinal photoreceptor, bipolar amacrine and ganglion cells [8,9]. The 224 amino acid RS polypeptide consists of a 23 amino acid leader sequence followed by a 39 amino acid RS domain, a highly conserved 157 amino acid discoidin domain and a 5 amino acid Ctermin...

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Novel mutations in XLRS1 causing retinoschisis, including first evidence of putative leader sequence change

Cited by 41 publications

References 22 publications

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

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

Mapping of Epitopes in Discoidin Domain Receptor 1 Critical for Collagen Binding

Identification and characterization of two mature isoforms of retinoschisin in murine retina

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