Molecular Mechanisms Leading to Null-protein Product from Retinoschisin (RS1) Signal-sequence Mutants in X-linked Retinoschisis (XLRS) Disease
Autor: | Paul A. Sieving, Lucia Ziccardi, Camasamudram Vijayasarathy, Richard A. Lewis, Ruifang Sui, Guoxing Yang, Yong Zeng, Rafael C. Caruso, Fei Xu |
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Jazyk: | angličtina |
Rok vydání: | 2010 |
Předmět: |
Male
Protein Folding Retinoschisis Molecular Sequence Data Codon Initiator Gene mutation Biology In Vitro Techniques Protein Sorting Signals Article Conserved sequence Chlorocebus aethiops Genetics medicine Electroretinography Animals Humans Point Mutation Amino Acid Sequence Eye Proteins Peptide sequence Genetics (clinical) Genetic Association Studies Base Sequence Point mutation Exons Genetic Therapy medicine.disease Phenotype Introns Recombinant Proteins Protein Structure Tertiary Amino Acid Substitution COS Cells RETINOSCHISIN Hydrophobic and Hydrophilic Interactions Discoidin domain |
Popis: | Retinoschisin (RS1) is a cell-surface adhesion molecule expressed by photoreceptor and bipolar cells of the retina. The 24-kDa protein encodes two conserved sequence motifs: the initial signal sequence targets the protein for secretion while the larger discoidin domain is implicated in cell adhesion. RS1 helps to maintain the structural organization of the retinal cell layers and promotes visual signal transduction. RS1 gene mutations cause X-linked retinoschisis disease (XLRS) in males, characterized by early-onset central vision loss. We analyzed the biochemical consequences of several RS1 signal-sequence mutants (c.1A>T, c.35T>A, c.38T>C, and c.52G>A) found in our subjects. Expression analysis in COS-7 cells demonstrates that these mutations affect RS1 biosynthesis and result in an RS1 null phenotype by several different mechanisms. By comparison, discoidin-domain mutations generally lead to nonfunctional conformational variants that remain trapped inside the cell. XLRS disease has a broad heterogeneity in general, but subjects with the RS1 null-protein signal-sequence mutations are on the more severe end of the clinical phenotype. Results from the signal-sequence mutants are discussed in the context of the discoidin-domain mutations, clinical phenotypes, genotype-phenotype correlations, and implications for RS1 gene replacement therapy. |
Databáze: | OpenAIRE |
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