The severity of retinal pathology in homozygous Crb1rd8/rd8 mice is dependent on additional genetic factors.
Bottom Line: This suggests that the Crb1(rd8/rd8) mutation is necessary, but not sufficient for the development of these degenerative features.By whole-genome SNP analysis of the genotype-phenotype correlation, a candidate region on chromosome 15 was identified.This study also provides insight into the nature of the retinal vascular lesions that likely represent a clinical correlate for the formation of retinal telangiectasia or Coats-like vasculopathy in patients with CRB1 mutations that are thought to depend on such genetic modifiers.
Affiliation: Department of Genetics and firstname.lastname@example.org.Show MeSH
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Mentions: To provide further insight into a potential genetic basis for the phenotypic variability, we decided to perform DNA SNP screen analysis for animals from the different lines. The SNP data confirmed the inbred status of the Crb1rd8/rd8/J line for which we observed a higher proportion of C3H (or identical) SNPs to be present than in the two other C57BL/6 Crb1rd8/rd8 lines (data not shown) suggesting that there are distinct genetic differences between the inbred Crb1rd8/rd8/J line and the two C57BL/6 Crb1rd8/rd8 lines (1) and (2) that are of common ancestry. Based on this common ancestry, and the distinct phenotypic differences shown by C57BL/6 Crb1rd8/rd8 line (1) and C57BL/6 Crb1rd8/rd8 line (2), we decided to generate preliminary data to help identify regions in the genome that may contain modifying factors. We therefore performed an ‘analysis of extremes’ using DNA SNP screen data from animals that are from either of the two related C57BL/6 Crb1rd8/rd8 lines (1) and (2), but show the most divergent (extremes) of the AF-lesion phenotype. Statistical analysis of this dataset identified a significant association between the genotype on a region of chromosome 15 and the phenotype (Table 2). As shown in Figure 7, there is a large region on chromosome 15 where mice with low AF-lesion count are homozygous for one allele (consistent with a C57BL/6 derived allele), whereas mice with a high AF-lesion number are either heterozygous or homozygous for alternative SNPs. These data suggest that this region on chromosome 15 may carry one or several genetic modifiers that determine the manifestation of the phenotype associated with the Crb1rd8/rd8 mutation.Table 2.