A novel achromatopsia mouse model resulting from a naturally occurring missense change in Cngb3
<strong>Purpose:</strong> 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 lo...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Association for Research in Vision and Ophthalmology
2018
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| _version_ | 1797098947058073600 |
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| author | Hassall, M Barnard, A Orlans, H McClements, M Charbel Issa, P Aslam, S Maclaren, R |
| author_facet | Hassall, M Barnard, A Orlans, H McClements, M Charbel Issa, P Aslam, S Maclaren, R |
| author_sort | Hassall, M |
| collection | OXFORD |
| description | <strong>Purpose:</strong> 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. <strong>Methods:</strong> 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. <strong>Results:</strong> 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. <strong>Conclusions:</strong> 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. |
| first_indexed | 2024-03-07T05:16:47Z |
| format | Journal article |
| id | oxford-uuid:dd7cb30b-57dc-40ea-a4c0-96d20aa33d0c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:16:47Z |
| publishDate | 2018 |
| publisher | Association for Research in Vision and Ophthalmology |
| record_format | dspace |
| spelling | oxford-uuid:dd7cb30b-57dc-40ea-a4c0-96d20aa33d0c2022-03-27T09:25:21ZA novel achromatopsia mouse model resulting from a naturally occurring missense change in Cngb3Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:dd7cb30b-57dc-40ea-a4c0-96d20aa33d0cEnglishSymplectic Elements at OxfordAssociation for Research in Vision and Ophthalmology2018Hassall, MBarnard, AOrlans, HMcClements, MCharbel Issa, PAslam, SMaclaren, R<strong>Purpose:</strong> 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. <strong>Methods:</strong> 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. <strong>Results:</strong> 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. <strong>Conclusions:</strong> 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. |
| spellingShingle | Hassall, M Barnard, A Orlans, H McClements, M Charbel Issa, P Aslam, S Maclaren, R A novel achromatopsia mouse model resulting from a naturally occurring missense change in Cngb3 |
| title | A novel achromatopsia mouse model resulting from a naturally occurring missense change in Cngb3 |
| title_full | A novel achromatopsia mouse model resulting from a naturally occurring missense change in Cngb3 |
| title_fullStr | A novel achromatopsia mouse model resulting from a naturally occurring missense change in Cngb3 |
| title_full_unstemmed | A novel achromatopsia mouse model resulting from a naturally occurring missense change in Cngb3 |
| title_short | A novel achromatopsia mouse model resulting from a naturally occurring missense change in Cngb3 |
| title_sort | novel achromatopsia mouse model resulting from a naturally occurring missense change in cngb3 |
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