Identification of a Major QTL, Which Modifies the Schisis and Layer Disorganization Phenotypes in Rs1htmgc1 Mice

Abstract

Purpose:: X-Linked Retinoschisis (XLRS) is a leading cause of inherited juvenile macular degeneration, which is characterized by a splitting of the retina (schisis), loss in central vision, and loss in the ERG b-wave. We study the Rs1h^tmgc1 mouse, which contains a splice site mutation that is similar to some mutations in human XLRS patients, as a model for XLRS. We noted a broad range of phenotypic severity in a mixed genetic background, which suggested the existence of genetic modifiers. The purpose of this study was to test whether the phenotypic variability is genetically based and to identify the loci underlying this variability.

Methods:: To map the genetic modifiers, we performed a whole genome wide scan using affected animals from an F2 intercross between Rs1h^tmgc1 and AKR/J mice. All F2 affected animals were phenotyped by histological analysis. Affected animals were scored for the degree of schisis, abnormal layer formation involving the ONL, and the existence of ectopic nuclei between the ONL and the RPE. Each mouse was given a phenotypic score between 0.5 and 3 depending on the severity of the phenotype. All genotypic and phenotypic information was analyzed by QTL Map Manager software version QTXb20.

Results:: We have identified one major QTL on chromosome 7 (F-score=113.3, LOD score= 24.6, p<1x10^-6). The AKR/J allele reduced the phenotypic severity of schisis and layer disorganization in a recessive fashion. This QTL is responsible for 46% of the phenotypic variance observed in this intercross, which suggests that a major locus is affecting the phenotypes. We named this QTL Mor1 for modifier of retinoschisis 1. Several candidate genes that are known to be involved in cell adhesion lie within the Mor1 minimal genetic region.

Conclusions:: The morphological phenotypes in Rs1h^tmgc1 mice are genetically modified by a major locus (Mor1) on chromosome 7, which may be involved in cell adhesion. Identification of the Mor1 gene should provide insight into the molecular mechanism of Rs1h mediated cell adhesion.

Keywords: gene modifiers • gene mapping • retinal adhesion