May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
A Novel ‘Knock-In’ Mouse Model for Cone Dystrophy: A Point Mutation in Guca1a Causes a Loss of Cone-Mediated Retinal Function and Photoreceptor Degeneration
Author Affiliations & Notes
  • P. K. Buch
    UCL Institute of Ophthalmology, London, United Kingdom
  • P. Cottrill
    UCL Institute of Ophthalmology, London, United Kingdom
  • S. E. Wilkie
    UCL Institute of Ophthalmology, London, United Kingdom
  • R. A. Pearson
    UCL Institute of Ophthalmology, London, United Kingdom
  • Y. Duran
    UCL Institute of Ophthalmology, London, United Kingdom
  • E. L. West
    UCL Institute of Ophthalmology, London, United Kingdom
  • S. S. Bhattacharya
    UCL Institute of Ophthalmology, London, United Kingdom
    NIHR Faculty, UCL/MEH London, United Kingdom
  • A. M. Dizhoor
    Pennsylvania College of Optometry, Elkins Park, Pennsylvania
  • R. R. Ali
    UCL Institute of Ophthalmology, London, United Kingdom
    NIHR Faculty, UCL/MEH London, United Kingdom
  • D. M. Hunt
    UCL Institute of Ophthalmology, London, United Kingdom
  • Footnotes
    Commercial Relationships  P.K. Buch, None; P. Cottrill, None; S.E. Wilkie, None; R.A. Pearson, None; Y. Duran, None; E.L. West, None; S.S. Bhattacharya, None; A.M. Dizhoor, None; R.R. Ali, None; D.M. Hunt, None.
  • Footnotes
    Support  Wellcome Trust, UK, Fighting Blindness Ireland and the Foundation Fighting Blindness, USA
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 4036. doi:https://doi.org/
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      P. K. Buch, P. Cottrill, S. E. Wilkie, R. A. Pearson, Y. Duran, E. L. West, S. S. Bhattacharya, A. M. Dizhoor, R. R. Ali, D. M. Hunt; A Novel ‘Knock-In’ Mouse Model for Cone Dystrophy: A Point Mutation in Guca1a Causes a Loss of Cone-Mediated Retinal Function and Photoreceptor Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4036. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : In order to accurately model cone dystrophy 3 (COD3), caused by an E155G substitution in the guanylate cyclase activating protein 1 (GCAP1), we created knock-in mice that have the same amino acid substitution. Here we present extensive, long-term characterization of the retinal phenotype.

Methods: : Mutant mice, generated using gene targeting, were genotyped using PCR and sequencing. Visual function was assessed using Ganzfeld electroretinography (ERG), and ocular morphology assessed using paraffin and resin-embedded sections. Immunohistochemistry was carried out on cryosections and retinal flatmounts.

Results: : We saw a progressive loss of cone-mediated ERG in heterozygous and homozygous mutant mice; b-wave amplitudes from 12 month-old mice were down to 17 % of wild-type. Mutant mice also lacked a flicker response to 10- and 15-Hz light stimuli, whereas wild-type litter-mates had a normal flicker. Rod-mediated b-wave amplitudes were also reduced in mutant mice, although in 12 month-old homozygous mice the rod dominated ERG was still 44 % of wild-type suggesting the mutation primarily affects cone function. Histological analysis showed significant loss of photoreceptor cells at five months of age, up to 47 % loss in homozygotes. We have also studied the effects of the mutation on rod recovery kinetics, photopigment expression, and retinal morphology.

Conclusions: : The analysis performed to date indicates that mice harbouring an E155G mutation in GCAP1 have a phenotype that is consistent with altered cone cell function. Further evaluation of this model using single-cell suction electrode recording, calcium imaging and biochemical analyses is now in progress.

Keywords: retinal degenerations: cell biology • transgenics/knock-outs • retina: distal (photoreceptors, horizontal cells, bipolar cells) 
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