June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
A naturally occurring mouse model of achromatopsia caused by a novel missense change in Cngb3.
Author Affiliations & Notes
  • Alun R Barnard
    Nuffield Lab of Ophthalmology, University of Oxford, Oxford, United Kingdom
    Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
  • Mark M Hassall
    Nuffield Lab of Ophthalmology, University of Oxford, Oxford, United Kingdom
  • Peter Charbel Issa
    Nuffield Lab of Ophthalmology, University of Oxford, Oxford, United Kingdom
    Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
  • Robert E MacLaren
    Nuffield Lab of Ophthalmology, University of Oxford, Oxford, United Kingdom
    Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
  • Footnotes
    Commercial Relationships   Alun Barnard, None; Mark Hassall, None; Peter Charbel Issa, None; Robert MacLaren, None
  • Footnotes
    Support  The Royal College of Surgeons of Edinburgh, The Rhodes Trust
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 1221. doi:
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      Alun R Barnard, Mark M Hassall, Peter Charbel Issa, Robert E MacLaren; A naturally occurring mouse model of achromatopsia caused by a novel missense change in Cngb3.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1221.

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

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Abstract

Purpose : A local colony of inbred mice (129S6/SvEvTac origin), previously bred in isolation for over a decade, were found to have completely absent light-adapted electroretinogram (ERG) responses. We investigated the inheritance and genetic basis of this cone photoreceptor function loss (cpfl) phenotype.

Methods : We performed ERG testing using an Espion E3 system. An affected 129S6/SvEvTac colony animal was outcrossed to a wild-type C57BL/6J mouse to produce first filial generation hybrid offspring (129SB6F1). The 129SB6F1 animals were intercrossed to investigate inheritance in the F2 generation. Targeted re-sequencing was performed on genes known to cause a cpfl phenotype and/or identified as causing achromatopsia in humans (Gnat2, Cnga3, Cngb3, Pde6c, Hcn1, Syne2). The eyes of selected animals underwent histological sectioning and cone arrestin immunostaining.

Results : All 129S6/SvEvTac colony animals tested lacked cone pathway ERG function (n= 12), although rod pathway ERG responses were unaffected. C57BL/6 outcross F1 progeny (129SB6F1) did not display a deficit in cone ERG function (n = 28). However, animals in the F2 generation showed the original cpfl phenotype, indicating a recessive inheritance pattern. DNA sequencing revealed that the colony did not carry cone gene mutations previous found in other inbred lines. Instead a novel missense mutation was identified in Cngb3. Genotyping 59 animals of the F2 generation found that: 15 were wildtype, 29 were heterozygous, 15 were homozygous for the novel Cngb3 mutation (not significantly different from expected 1:2:1 ratio, X = 0.9745, df = 2, p = 0.6143). Animals that were wildtype or heterozygous had normal cone ERGs, whereas all F2 animals homozygous for the Cngb3 mutation showed the cpfl phenotype. There was no obvious retinal degeneration and cone photoreceptors with normal morphology were present in all eyes examined.

Conclusions : We identified a novel missense mutation in the Cngb3 gene, which results recessive inheritance of cone pathway function loss in mice. The human condition of CNGB3 achromatopsia is predominantly one of missense changes, presumed to result in the production of non-functional protein in cones, rather than null mutations. Hence, this naturally occurring achromatopsia mouse more closely represents the human disease and may be a more informative model against which to assess the potential effects of CNGB3 gene therapy.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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