The severity of retinal pathology in homozygous Crb1rd8/rd8 mice is dependent on additional genetic factors

Ulrich F O Luhmann, Livia S Carvalho, Sophia-Martha Kleine Holthaus, Jill A Cowing, Simon Greenaway, Colin J Chu, Philipp Herrmann, Alexander J Smith, Peter M G Munro, Paul Potter, James W B Bainbridge, Robin R Ali

Research output: Contribution to journalArticle (Academic Journal)peer-review

40 Citations (Scopus)
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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 Crb1(rd8/rd8) mutation, we compared the retinal pathology of Crb1(rd8/rd8)/J inbred mice with that of two Crb1(rd8/rd8) lines backcrossed with C57BL/6JOlaHsd mice. Topical endoscopic fundal imaging and scanning laser ophthalmoscopy fundus images of all three Crb1(rd8/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 Crb1(rd8/rd8) line, even at 12 months of age. 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 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.

Original languageEnglish
Article numberddu424
Pages (from-to)128-141
Number of pages14
JournalHuman Molecular Genetics
Issue number1
Early online date21 Aug 2014
Publication statusPublished - 1 Jan 2015


  • Animals
  • Chromosomes, Mammalian
  • Fluorescein Angiography
  • Genetic Association Studies
  • Humans
  • Mice
  • Mice, Inbred Strains
  • Mutation
  • Nerve Tissue Proteins
  • Ophthalmoscopes
  • Photoreceptor Cells, Vertebrate
  • Polymorphism, Single Nucleotide
  • Retina
  • Retinal Diseases
  • Retinal Vessels


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