2.2.2. PDE6B

The catalytic beta subunit (PDE6B) of the cGMP-PDE heteromeric holoenzyme is another essential component of the rod photoreceptor phototransduction cascade located in the outer segments [33]. Mutations in the gene encoding for Pde6b causes PRA (rod–cone dysplasia type 1, *rcd1*) in the Irish Setter dog [38,45,46] which is a model for RP40 in humans. RP40 is one of the most common autosomal recessive RPs leading to blindness in midlife in humans. As with the *Pde6a*−/− dog, rod photoreceptors are a ffected first, then cones later in the disease [47,48]. The *Pde6b*−/− dog phenotype has an autosomal recessive mode of inheritance and is caused by a nonsense mutation (c.2420G>A, p.Trp807Ter) [38,45]. This truncated protein would lack the C-terminal domain that is required for posttranslational processing and membrane association. The failure of phosphodiesterase activity due to a lack of function in Pde6b leads to elevated cGMP levels from an early age [47,49]. The elevation of cGMP in rods as they develop outer segments results in the halting of outer segmen<sup>t</sup> elongation followed by rod degeneration, starting in the central retina first, then spreading to the entire retina following the same pattern of rod maturation. The cone outer segmen<sup>t</sup> development is also halted and, with the loss of the rods, the genetically una ffected cone photoreceptors also progressively degenerate [46,47]. Interestingly, in contrast to the *Pde6a*−/− dog retina where the lack of Pde6a leads to the absence of both alpha and beta Pde6 subunits, the *Pde6b*−/− dog retina has a detectable Pde6a subunit in Western blot, prior to rod degeneration [38]. Therefore, it appears that the alpha subunit is necessary for the beta subunit to be maintained, while the beta subunit is not essential for the maintenance of the alpha subunit. Adeno-associated gene therapy has been shown to halt retinal degeneration in the *rcd1* dog [50].

Mutations in *Pde6b* have been identified in at least two other breeds of dogs (Sloughi and American Sta ffordshire terriers; see Table 1 for mutation information) [51,52].
