Molecular mechanisms leading to null-protein product from retinoschisin (RS1) signal-sequence mutants in X-Linked Retinoschisis (XLRS) disease

Camasamudram Vijayasarathy, Ruifang Sui, Yong Zeng, Guoxing Yang, Fei Xu, Rafael C. Caruso, Richard A. Lewis, Lucia Ziccardi, Paul A. Sieving

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1251-1260
Number of pages10
JournalHuman Mutation
Volume31
Issue number11
DOIs
Publication statusPublished - Nov 2010

Keywords

  • Discoidin
  • Retinoschisin
  • Signal sequence
  • Splicing
  • X-linked retinoschisis
  • XLRS

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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