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Abstract
Understanding phenotype–genotype correlations in retinal degeneration is a major challenge. Mutations in CRB1 lead to a spectrum of autosomal recessive retinal dystrophies with variable phenotypes suggesting the influence of modifying factors. To establish the contribution of the genetic background to phenotypic variability associated with the Crb1rd8/rd8 mutation, we compared the retinal pathology of Crb1rd8/rd8/J inbred mice with that of two Crb1rd8/rd8 lines backcrossed with C57BL/6JOlaHsd mice. Topical endoscopic fundal imaging and scanning laser ophthalmoscopy fundus images of all three Crb1rd8/rd8 lines showed a significant increase in the number of inferior retinal lesions that was strikingly variable between the lines. Optical coherence tomography, semithin, ultrastructural morphology and assessment of inflammatory and vascular marker by immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction revealed that the lesions were associated with photoreceptor death, Müller and microglia activation and telangiectasia-like vascular remodelling—features that were stable in the inbred, variable in the second, but virtually absent in the third Crb1rd8/rd8 line, even at 12 months of age. This suggests that the Crb1rd8/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 may carry one or more genetic modifiers for the manifestation of the retinal pathology associated with mutations in Crb1. 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.
Highlights
Understanding the genotype – phenotype correlation in retinal degenerations remains a major challenge even for monogenetic diseases
To establish the contribution of the genetic background to phenotypic variability associated with the Crb1rd8/rd[8] mutation, we compared the retinal pathology of Crb1rd8/rd8/J inbred mice with that of two Crb1rd8/rd[8] lines backcrossed with C57BL/6JOlaHsd mice
We describe primary consequences of the Crb1rd8/rd[8] mutation, identify secondary phenotypic features that did not manifest in all Crb1rd8/rd[8] lines and identify a candidate region on chromosome 15 that may carry additional genetic factors that determine the severity of the retinal pathology caused by mutations in Crb[1]
Summary
Understanding the genotype – phenotype correlation in retinal degenerations remains a major challenge even for monogenetic diseases. The causality of many primary mutations has been convincingly established, the clinical manifestation of even identical mutations can be highly variable. This may be due to additional genetic polymorphisms in the same gene (allelic heterogeneity) or in additional genes (genetic modifiers) as well as environmental factors. One example of mutations in a gene that lead to a highly variable spectrum of clinical phenotypes is the CRB1 gene (OMIM #604210). They typically cause a spectrum of autosomal recessive
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