Residual rod function in CNGB1 mutant dogs

• Published in: Documenta ophthalmologica Vol. 145; no. 3; pp. 237 - 246
• Main Authors: Petersen-Jones, Simon M., Pasmanter, Nathaniel, Occelli, Laurence M., Querubin, Janice R., Winkler, Paige A.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-12-2022; Springer Nature B.V
• Subjects: Animal models; Animals; Cyclic Nucleotide-Gated Cation Channels - genetics; Disease Models, Animal; Dogs; Electroretinograms; Electroretinography; Immunohistochemistry; Light effects; Medicine; Medicine & Public Health; Mutants; Mutation; Ophthalmology; Original Research Article; Phosphodiesterase; Retinal Cone Photoreceptor Cells; Retinitis; Retinitis pigmentosa; Retinitis Pigmentosa - genetics; Retinitis pigmentosa; Electroretinogram; Rod; Dog-model; CNGB1
• ISSN: 0012-4486; 1573-2622
• DOI: 10.1007/s10633-022-09899-3

Purpose
Mutations in the cyclic nucleotide-gated (CNG) channel beta subunit (
CNGB1
) are an important cause of recessive retinitis pigmentosa. We identified a large animal model with a truncating mutation of
CNGB1
. This study reports the persistence of small, desensitized rod ERG responses in this model.
Methods
Dark-, light-adapted and chromatic ERGs were recorded in
CNGB1
mutant dogs and age and breed matched controls. Comparisons were made with a dog model known to completely lack rod function; young dogs with a mutation in the rod phosphodiesterase 6 alpha subunit (
PDE6A
−/−
). Immunohistochemistry (IHC) to label the rod CNG alpha (CNGA1) and CNGB1 subunits was performed.
Results
The dark-adapted ERG of
CNGB1
mutant dogs had a raised response threshold with lack of normal rod response and a remaining cone response. Increasing stimulus strength resulted in the appearance of a separate, slower positive waveform following the dark-adapted cone b-wave. With increasing stimulus strength this increased in amplitude and became faster to merge with the initial b-wave. Comparison of responses from
PDE6A
−/−
(cone only dogs) with
CNGB1
mutant dogs to red and blue flashes and between dark-adapted and light-adapted responses supported the hypothesis that the
CNGB1
mutant dog had residual desensitized rod responses.
CNGB1
mutant dogs had a small amount of CNGA1 detectable in the outer segments.
Conclusions
CNGB1
mutant dogs have a residual ERG response from desensitized rods. This may be due to low levels of CNGA1 in outer segments.