*4.2. CNGB1*

There are three splice variants of *CNGB1* expressed in the retina, glutamic acid rich proteins (GARPs) GARP1, GARP2 and CNGB1a. The full-length protein, CNGB1a, is part of the heterotetrameric CNG channel of the rod photoreceptor [72]. A complex mutation in *Cngb1* was identified in Papillon dogs with PRA. The mutation identified in these dogs is a 6 bp insertion accompanied by a 1 bp deletion, predicted to result in a frameshift and a premature stop codon, six amino acids downstream [77]. Upon further analysis of the *Cngb1a* transcript in the *Cngb1*−/− dogs, it was found that the mutation led to the skipping of exon 26, resulting in a premature stop codon early in exon 27. A truncated Cngb1a protein is produced, but does not form channels with Cnga1 and remains in the inner segments of the rod photoreceptors [78]. Mutations in *CNGB1* cause RP45 in humans, which represents less than 4% of arRP cases [39].

Human RP45 patients with mutations downstream of the GARP splice variants, the mouse knockout model (*Cngb1-X26*) and the *Cngb1*−/− dog have similar phenotypes [78,79]. The canine model shows a slow loss of rod photoreceptors and the relative preservation of cones, particularly in the area centralis and visual streak. Cone function decreases as the disease progresses, as assessed by ERG, but cone-led vision remains normal, at least up to four years [77]. Preliminary gene therapy trials have shown that treatment at 3.5–6.5 months of age in a ffected dogs rescues vision and slows the progression of the disease in the treated areas [78].

Both the slow disease progression and the large treatment window (in dogs and anticipated in humans [80]) make the *Cngb1*−/− dog an ideal model for studying therapies and outcome measures.
