Targeted Ablation of the Pde6h Gene in Mice Reveals Cross-species Differences in Cone and Rod Phototransduction Protein Isoform Inventory

Abstract Phosphodiesterase-6 (PDE6) is a multi-subunit enzyme that plays a key role in the visual transduction cascade in rod and cone photoreceptors. Each type of photoreceptor utilizes discrete catalytic and inhibitory PDE6 subunits to fulfil its physiological tasks i.e. the degradation of cyclic guanosine-3′,5′-monophosphate at specifically tuned rates and kinetics. Recently, the human PDE6H gene was identified as a novel locus for autosomal-recessive (incomplete) colour-blindness. However, the three different classes of cones were not affected to the same extend: Short-wave (S) cone function was more preserved than middle- and long-wave (M, L) cone function indicating that some basic regulation of the PDE6 multi-subunit enzyme was maintained albeit by a unknown mechanism. To study normal and disease-related functions of cone Pde6h in vivo we generated Pde6h knockout (Pde6h-/-) mice. Expression of PDE6H in murine eyes was restricted to both segments and synapses of S- and L/M-cone photoreceptors, whereas Pde6h-/- retinas remained PDE6H-negative. Combined in vivo assessment of retinal morphology with histomorphological analyses reveal a normal overall integrity of the retinal organization and an unaltered distribution of the different cone photoreceptor subtypes upon Pde6h ablation. In contrast to human patients, our electroretinographic examinations of Pde6h-/- mice suggest no defects in cone/rod-driven retinal signaling and therefore preserved visual functions. To this end, we were able to demonstrate presence of rod PDE6G in cones indicating functional substitution of PDE6. The disparities between human and murine phenotypes caused by mutant Pde6h/PDE6H suggest species-to-species differences in the vulnerability of biochemical and neurosensory pathways of the visual cycle.