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

Autor:	Luhmann UF; Department of Genetics and u.luhmann@ucl.ac.uk., Carvalho LS; Department of Genetics and., Holthaus SM; Department of Genetics and MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK., Cowing JA; Department of Genetics and., Greenaway S; Imaging Unit, UCL Institute of Ophthalmology, London EC1V 9EL, UK., Chu CJ; Department of Genetics and., Herrmann P; Department of Genetics and., Smith AJ; Department of Genetics and., Munro PM; Imaging Unit, UCL Institute of Ophthalmology, London EC1V 9EL, UK., Potter P; Mammalian Genetics Unit, MRC Harwell, Oxfordshire OX11 ORD, UK and., Bainbridge JW; Department of Genetics and NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London EC1V 2PD, UK., Ali RR; Department of Genetics and NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London EC1V 2PD, UK.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2015 Jan 01; Vol. 24 (1), pp. 128-41. Date of Electronic Publication: 2014 Aug 21.
DOI:	10.1093/hmg/ddu424
Abstrakt:	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. (© The Author 2014. Published by Oxford University Press.)
Databáze:	MEDLINE
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