Originally published as Genetics Published Articles Ahead of Print on February 3, 2008.

Genetics, Vol. 178, 1785-1794, March 2008, Copyright © 2008
doi:10.1534/genetics.107.084905

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

Britt A. Johnson, Natsuyo Aoyama, Nicole H. Friedell, Sakae Ikeda and Akihiro Ikeda1

Department of Medical Genetics, University of Wisconsin, Madison, Wisconsin 53706

1 Corresponding author: Department of Medical Genetics, Room 5350 Genetics/Biotech, 425-G Henry Mall, University of Wisconsin, Madison, WI 53706.
E-mail: aikeda{at}wisc.edu

X-linked retinoschisis (XLRS) is an inherited form of macular degeneration that is caused by mutations in the retinoschisin (RS1) gene. In addition to macular degeneration, other major characteristics of XLRS include splitting of the retina (schisis) and impaired synaptic transmission as indicated by a reduction in the electroretinogram b-wave. It has been known that patients carrying RS1 mutations show a broad range of phenotypic variability. Interestingly, phenotypic variation is observed even among family members with the same RS1 mutation, suggesting the existence of genetic or environmental factors that contribute to the severity of XLRS. However, in the human population, the cause of phenotypic variability and the contribution of genetic modifiers for this relatively rare disease are difficult to study and poorly understood. In this study, using a mouse model for XLRS, we show that genetic factors can contribute to the severity of the retinoschisis phenotype. We report evidence of a major genetic modifier of Rs1, which affects the disease severity in these animals. A quantitative trait locus (QTL), named modifier of Rs1 1 (Mor1), is mapped on chromosome (Chr) 7. When homozygous, the Mor1 allele from the inbred mouse strain AKR/J diminishes the severity of the schisis phenotype in Rs1tmgc1/Y male and Rs1tmgc1/Rs1tmgc1 female mice. We also show that the penetrance of the disease phenotype is affected by additional genetic factor(s). Our study suggests that multiple genetic modifiers could potentially be responsible for the phenotypic variation in human XLRS.