Our studies are specifically focused on understanding the molecular mechanisms causing human retinal diseases associated with synaptic functional and structural defects. X-linked retinoschisis (XLRS) is a common inherited macular degenerative disease caused by mutations in the RS1 gene. In humans, affected individuals show a significant loss in central vision at early stages of life with a splitting of the inner layers of the retina, and a loss in the b-wave of the electroretinogram (ERG). Loss of the b-wave indicates functional abnormalities in the synaptic interactions. Although RS1 function is predicted to be associated with cell adhesion, molecular pathways underlying the disease and the normal function of RS1 are largely unknown. We recently identified a new allele of the mutation in the RS1 mouse ortholog, Rs1h, in 44TNJ mice created by ENU mutagenesis. Synaptic abnormalities as well as severe cell adhesion and retinal laminar structure defects in mutant mice have been observed. In the course of positional cloning, we also identified a single major modifier locus that changes the schisis phenotype and laminar structure abnormality. The goal of this project is to understand the molecular pathway through which the RS1 gene functions using mouse molecular genetic approaches. Our hypothesis is that RS1H maintains the functional and structural integrity of the retinal layers, including the synaptic function, through its role in cell adhesion, which is regulated by genetically and physically interacting factors. In this proposal, our main focus is to identify and characterize the modifier of the Rs1h 1 (Mori) gene.
In Aim 1, we will conduct positional cloning to identify the Mori gene.
In Aim 2, we will test interaction between RS1H and candidates for RS1H binding proteins. Further, we will test the effect of the modifier gene on phenotypes caused by a mutation in Rs1h and a candidate RS1H binding molecule. ? ? ?
|Johnson, Britt A; Cole, Brian S; Geisert, Eldon E et al. (2010) Tyrosinase is the modifier of retinoschisis in mice. Genetics 186:1337-44|
|Johnson, Britt A; Aoyama, Natsuyo; Friedell, Nicole H et al. (2008) Genetic modification of the schisis phenotype in a mouse model of X-linked retinoschisis. Genetics 178:1785-94|
|Johnson, Britt A; Ikeda, Sakae; Pinto, Lawrence H et al. (2006) Reduced synaptic vesicle density and aberrant synaptic localization caused by a splice site mutation in the Rs1h gene. Vis Neurosci 23:887-98|