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Mark M. Hassall, Alun R. Barnard, Harry O. Orlans, Michelle E. McClements, Peter Charbel Issa, Sher A. Aslam, Robert E. MacLaren; A Novel Achromatopsia Mouse Model Resulting From a Naturally Occurring Missense Change in Cngb3. Invest. Ophthalmol. Vis. Sci. 2018;59(15):6102-6110. doi: 10.1167/iovs.18-24328.
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A local colony of inbred mice (129S6/SvEvTac origin), in isolation for over a decade, were found to have absent light-adapted electroretinogram (ERG) responses. We investigated the inheritance and genetic basis of this phenotype of cone photoreceptor function loss.
An affected 129S6/SvEvTac colony animal was outcrossed to a C57BL/6J mouse and intercrossed to investigate inheritance in the F2 generation. We performed ERG testing and targeted resequencing on genes of interest (Gnat2, Cnga3, Cngb3, Pde6c, Hcn1, Syne2). The eyes of a subset of animals underwent histologic immunostaining.
All 129S6/SvEvTac colony animals tested lacked cone pathway function by ERG testing (n = 12), although rod pathway–based ERG responses remained unaffected. Outcross-intercross breeding showed a recessive inheritance pattern. A novel missense mutation was identified in the Cngb3 gene, which causes an amino acid substitution at a conserved residue (NM_013927)c.692G>A; p.(R231H). The recessive phenotype only affected homozygotes (χ2 = 39, P = 3.2e−10). Cones had normal morphology at postnatal day (PND) 70, but cone cell counts declined from PND 30 to PND 335 (P = 0.038), indicating progressive cone photoreceptor death.
We identified the spontaneous occurrence of a 10th model of cone photoreceptor function loss (cpfl10) in an isolated line of inbred mice. Our results indicate that this is caused by a novel missense mutation in the Cngb3 gene, with a fully recessive inheritance pattern. This mouse may provide a more appropriate background against which to assess CNGB3 achromatopsia gene therapy for missense mutations.
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