Genetic Modification of the Schisis Phenotype in a Mouse Model of X-Linked Retinoschisis

Abstract

Purpose: : X-linked retinoschisis (XLRS) is an inherited form of macular degeneration that is caused by mutations in the retinoschisis 1 (RS1) gene. A major feature of this disease is splitting (schisis) of the retina. Patients with XLRS exhibit a broad range of phenotypic variability, even among family members with the same mutation, which suggests the existence of genetic modifiers. Previously, we reported the identification of a major QTL, named Mor1, which modifies the schisis phenotype in a mouse model of XLRS, the Rs1^tmgc1 mouse. The purpose of this study was to further test the effect of Mor1 and the genetic background on the schisis phenotype in mutant mice. Since Rs1^tmgc1 mice have a splice site mutation, we also examined whether allelic differences at the Mor1 locus affect the splice variants of Rs1 transcripts in Rs1^tmgc1 mice.

Methods: : B6 congenic mice that carry the Rs1^tmgc1 mutation and were either AKR, B6, or heterozygous for Mor1 were generated. C3H congenic mice that carry the Rs1^tmgc1 mutation were also generated. To examine the population of Rs1 splice variants in mutant mice, we performed fragment analysis of Rs1 transcripts using an Agilent 2100 Bioanalyzer.

Results: : The schisis phenotype isrescued in B6 congenic Rs1^tmgc1 mice homozygous for the protective allele of Mor1. Rs1^tmgc1 mice congenic on a C3H background have a higher penetrance of the schisis phenotype compared to those congenic on a B6 background. Fragment analysis showed that allelic differences at the Mor1 locus do not affect the Rs1 splice variants in mutant animals.

Conclusions: : Our results show that a single genetic locus, Mor1, can specifically modify cell adhesion in Rs1^tmgc1 mice. Another modifier(s) may exist, which changes the penetrance of the schisis phenotype in B6 and C3H congenic mice. Since the allelic differences of Mor1 do not change the splicing population of Rs1 transcripts in Rs1^tmgc1 mice, it is unlikely that the splicing machinery is involved in the function of Mor1. Identification of Mor1 may provide insight into the genetic basis of phenotypic variability observed in human XLRS patients.

Keywords: genetics • gene modifiers • retinal adhesion