Molecular Mechanisms Leading to Null-Protein Product from Retinoschisin (RS1) Signal-Sequence Mutants in X-Linked Retinoschisis (XLRS) Disease

• Published in: Human mutation Vol. 31; no. 11; pp. 1251 - 1260
• Main Authors: Vijayasarathy, Camasamudram, Sui, Ruifang, Zeng, Yong, Yang, Guoxing, Xu, Fei, Caruso, Rafael C., Lewis, Richard A., Ziccardi, Lucia, Sieving, Paul A.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.11.2010; John Wiley & Sons, Inc
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Animals; Base Sequence; Chlorocebus aethiops; Codon, Initiator - genetics; COS Cells; discoidin; Electroretinography; Exons; Eye Proteins - chemistry; Eye Proteins - genetics; Eye Proteins - metabolism; Genetic Association Studies; Genetic Therapy; Genotype & phenotype; Humans; Hydrophobic and Hydrophilic Interactions; In Vitro Techniques; Introns; Male; Molecular Sequence Data; Mutation; Point Mutation; Protein Folding; Protein Sorting Signals - genetics; Protein Structure, Tertiary; Proteins; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; retinoschisin; Retinoschisis - genetics; Retinoschisis - pathology; Retinoschisis - physiopathology; Retinoschisis - therapy; signal sequence; splicing; X-linked retinoschisis; XLRS
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.21350

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. Hum Mutat 31:1251–1260, 2010. Published 2010 Wiley‐Liss, Inc.