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: The development of additional degenerative features during progression of the degeneration in different Crb1rd8/rd8 lines was assessed by AF-SLO and OCT imaging of animals of 12 months of age and by evaluating retinal sections and flat mount preparations for aberrant vascular features using lectin B4 and CD31 labelling (Fig. 6). Mice from all lines showed at 12 months very similar inferior retinal phenotypes as at 2 months of age (Fig. 6 versus Fig. 1). The inbred Crb1rd8/rd8/J and the C57BL/6 Crb1rd8/rd8 (2) lines showed again the prominent irregular lesions in the inferior retina (Fig. 6A and B, red arrows), while mice from the C57BL/6 Crb1rd8/rd8 (1) line still only revealed very few small or even no inferior lesions (Fig. 6C, red arrow). However, all Crb1rd8/rd8 lines showed a variable, but significant increase in additional distinct autofluorescent spots across the whole fundus indicating an accumulation of subretinal microglia/macrophages in all lines compared with age-matched wild-type mice (Fig. 6Ai–Di and E) (19). As early as 2 months, local microglia (Fig. 6F) and Müller glial activation (Fig. 6G) inside the large inferior retinal lesions were closely associated with aneurysm-like vascular structures derived from deep retinal capillaries (Fig. 6H) and with even larger vessels that extend through holes in the ONL towards the RPE (Fig. 6I, arrow). Such vessels were also seen at 12 months in severely affected Crb1rd8/rd8 mice, but then extend from a strongly remodelled vascular bed (Fig. 6J–L). These vessels do not break through Bruch's membrane according to our previous analysis of this type of lesion (20). In contrast, C57BL/6 Crb1rd8/rd8 (1) mice at 2 and 12 months of age did not show prominent vascular remodelling or microglia activation apart from a rare manifestation of a few small aneurysms at the OPL (Fig. 5Ci), but rather showed the three-layered vasculature typical of wild-type mice (Fig. 6M).Figure 6.