Mapping Genetic Modifiers Affecting Photoreceptor Degeneration and Axial Length in Eyes from Homozygous Mfrprd6 Mice

MFRP (Membrane Frizzled-Related Protein) is a member of the frizzled-related family of proteins with currently unknown molecular function in the eye. Mutations in the MFRP gene in humans cause microphthalmia, nanophthalmia, retinitis pigmentosa, and foveoschisis, and are also associated with refractive errors. The clinical presentations among patients with MFRP mutations varies, with some showing one of the abnormalities and others combinations of disease phenotypes, suggesting the action of modifier genes. Unlike genetic studies in humans, localization and eventual identification of modifier genes in mouse models is straightforward. Here we report the chromosomal localization of five novel quantitative trait loci (QTL) affecting the degree of photoreceptor degeneration and axial length in a mouse model carrying the homozygous Mfrprd6 allele. QTL analysis was performed on genotype and phenotype data from 225 F2 progeny homozygous for the Mfrprd6 mutant allele derived from an intercross of (B6.Cg-Mfrprd6/rd6 × C3A.BLiA-Pde6b+/J) F1 mice. Three QTL peaks were detected for number of photoreceptor nuclei, a measure of retinal degeneration, on Chr2 (53.3 centimorgan (cM)), Chr4 (56.6 cM), and Chr12 (45.5 cM). Two QTL were detected for axial length on Chr3 (49.5 cM) and Chr19 (24.5 cM). The results demonstrate that diverse Mfrp-associated disease phenotypes can be genetically modified, indicating that genetic variation underlies phenotypic variation.