Purchase this article with an account.
M. Danciger, H. Yang, R. Ralston, Y. Liu, M. T. Matthes, D. Yasumura, M. M. LaVail; Discovery of QTL That Modify rd3-Induced Retinal Degeneration in the Mouse Model; Several Are in Common With QTL Affecting Age-Related Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4633.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Previously, we showed that rd3 retinal degeneration progresses significantly more slowly in C57BL/6-c2J (B6/c) than in BALB/cByJ (BALB) albino mice. At P70 in particular, the thickness of the retinal outer nuclear layer (ONL) in N10 BALB, rd3/rd3 retinas is ~50% that of N10 B6/c, rd3/rd3. The purpose of this work was to identify the chromosomal loci (QTL) of the genes/alleles that influence rd3-induced retinal degeneration (rd3-RD). The discovery of these QTL is the first step toward identifying the mouse modifier genes (and their human orthologs) that influence the course and severity of a model inherited retinal degeneration.
Starting with Rb4Bnr rd3/rd3 (a mixed strain background), the rd3 allele was bred into BALB or into B6/c to N10. At P69-71, the ONL was measured in 431 F2 progeny of a reciprocal F1 intercross between N10 B6/c, rd3/rd3 and N10 BALB, rd3/rd3. Genomic DNAs from the F2 progeny were genotyped with 877 SNPs comprising a genome-wide scan with an average spacing of 2.0 cM and 2.9 Mb. The data was analyzed with the Map Manager QTX program.
Six highly significant QTL influencing rd3-RD were detected. Four on mouse Chrs 17, 8, 14 and 6 represented B6/c gene alleles that protected against rd3-RD, while the fifth and sixth both on Chr 5 represented B6/c alleles that made the retina more sensitive. The LOD scores and percent effects for the protective B6/c QTL were 19.2/19%, 16.0/11%, 8.2/5%, 6.3/3%, respectively, and for the B6/c sensitivity alleles 21.8/17% and 5.2/3%. Additionally, two suggestive B6/c protective QTL were found on Chrs 19 and 7. The QTL on Chrs 17, 8 and 14 overlap QTL from previous age-related retinal degeneration (age-RD) studies and the Chr 6 QTL overlaps QTL from previous age-RD and light-induced RD (LD-RD) studies.
The discovery of the rd3-RD QTL represents the first step toward identifying the modifier genes that influence this model retinal degeneration. The presence of three QTL in common between age-RD and rd3-RD and one QTL common to age-RD, LD-RD and rd3-RD suggests that all three types of retinal degeneration and particularly the mutation-induced rd3-RD and age-RD have significant genetic elements in common. The identification of these mouse modifier gene elements common to 2 or 3 retinal degeneration pathways and their human orthologs will open avenues of study designed to identify therapeutic regimens of broad effect.
This PDF is available to Subscribers Only