2.2.1. PDE6A

A dog model with a null mutation in the gene encoding for Pde6a has been identified. It has a relatively severe phenotype and is a model for RP43 in humans [34,35]. This form of PRA was given the name rod–cone dysplasia type 3 (*rcd3*). The frameshift mutation, c.1939delA. p.Asn616ThrfsTer39, results in the absence of Pde6a in the a ffected dog retina (*Pde6a*−/−) [35]. Western blot analysis shows the absence of all Pde6 subunits, showing the requirement of Pde6a for stability and normal tra fficking of Pde6b [35]. In the absence of the Pde6 holoenzyme, the cGMP hydrolyzing activity is absent and cGMP accumulates in the rod photoreceptors [41]. Increased cGMP is a well-established cause of photoreceptor cell death, likely due to the increased influx of calcium ions into the outer segmen<sup>t</sup> [42], triggering apoptosis [43]. The rod outer segments fail to mature in *Pde6a*−/− dogs and the genetically una ffected cones have stunted outer segments, which is reflected in a reduction in cone electroretinogram (ERG) a-waves early in the disease process [35]. Following the death of rod photoreceptors, there is a progressive loss of cones, which is reflected in the declining cone ERG amplitudes which eventually become undetectable at about one year of age (SMPJ unpublished data). Adeno-associated gene therapy was able to rescue rod function and promote cone function, as well as preserve retinal morphology [41,44].
