title: The severity of retinal pathology in homozygous Crb1rd8/rd8 mice is dependent on additional genetic factors.
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 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.
authors.affiliation: Department of Genetics and u.luhmann@ucl.ac.uk.
authors.forename: Ulrich F O
authors.initials: UF
authors.lastname: Luhmann
authors.affiliation: Department of Genetics and.
authors.forename: Livia S
authors.initials: LS
authors.lastname: Carvalho
authors.affiliation: Department of Genetics and MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
authors.forename: Sophia-Martha Kleine
authors.initials: SM
authors.lastname: Holthaus
authors.affiliation: Department of Genetics and.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Cowing
authors.affiliation: Imaging Unit, UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Greenaway
authors.affiliation: Department of Genetics and.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Chu
authors.affiliation: Department of Genetics and.
authors.forename: Philipp
authors.initials: P
authors.lastname: Herrmann
authors.affiliation: Department of Genetics and.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Smith
authors.affiliation: Imaging Unit, UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Peter M G
authors.initials: PM
authors.lastname: Munro
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Oxfordshire OX11 ORD, UK and.
authors.forename: Paul
authors.initials: P
authors.lastname: Potter
authors.affiliation: Department of Genetics and NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London EC1V 2PD, UK.
authors.forename: James W B
authors.initials: JW
authors.lastname: Bainbridge
authors.affiliation: Department of Genetics and NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London EC1V 2PD, UK.
authors.forename: Robin R
authors.initials: RR
authors.lastname: Ali
mesh_terms: D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics*; D005451:Fluorescein Angiography; D056726:Genetic Association Studies; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D019721:Ophthalmoscopes; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012160:Retina / Q000378:metabolism / Q000473:pathology*; D012164:Retinal Diseases / Q000235:genetics*; D012171:Retinal Vessels / Q000473:pathology
chemical_list: C453730:Crb1 protein, mouse; D009419:Nerve Tissue Proteins