Highly Significant QTLs on Mouse Chrs 4 and 6 that Influence Light-induced Retinal Degeneration; Comparison with Age-related Retinal Degeneration QTLs

Abstract

Abstract: : Purpose: BALB/cByJ (BALB/c) retinas are significantly more susceptible to light insult than those of 129S1/SvImJ (129). The purpose of this work was to determine the quantitative trait loci (QTLs) that influence intense light-induced retinal degeneration (LRD) as a first step toward identifying the genes/alleles they represent. Methods: 289 F2 progeny of an intercross between the 129 and BALB/c strains aged to approximately 6 weeks were exposed to 15,000 LUX of light for 1 hour after their pupils were dilated, and then placed in the dark for 16 hours. After 10-12 days of dim cyclic light, the amount of rhodopsin remaining in the retinas was measured spectrophotometrically. This was used as the trait quantitating the degree of retinal degeneration. Among the F2 progeny, neither gender nor pigmentation had a significant influence on the amount of rhodopsin loss after light exposure. For genetic study, DNAs from F2 progeny were genotyped with more than 100 dinucleotide repeat markers spanning the genome. For screening purposes, the markers were first tested in 27 F2 progeny with the most rhodopsin remaining and the 27 F2 progeny with the least rhodopsin. Any marker with a 95% probability of being associated with phenotype was tested in all F2 progeny. Data were analyzed with the Map Manager QTX program. Results: Two QTL's on mouse Chrs 4 and 6 were identified. Each accounted for a substantial portion of the total genetic effect influencing LRD, and each represented genes with BALB/c susceptible (or 129 protective) alleles. As expected, there was no QTL at the locus of the Rpe65 gene that strongly influenced LRD in a study of C57BL/6J- c2J (c2J) and BALB/c, since 129 has the LEU450 variant of the gene (as does BALB/c). The Chr 4 locus was not present in the c2J-BALB/c LRD study, nor in an age-related retinal degeneration (ARD) study between the same two strains. However, the Chr 6 QTL, appeared to be in the same locus as a highly significant QTL influencing age-related retinal degeneration (ARD), and both represented a gene with a recessive, BALB/c susceptible allele. Conclusions: Although many of the (genes in) QTLs that influence LRD and ARD are in loci distinct from one another, there is at least one QTL locus common to both light-induced and age-related retinal degeneration susceptibility.

Keywords: radiation damage: light/UV • animal model • genetics