Visual acuities in patients with autosomal recessive retinitis pigmentosa associated with four rod phototransduction genes

Inherited retinal diseases (IRDs) are a leading cause of vision impairment in children and working-age adults in several countries.Retinitis pigmentosa (RP) is the most frequent phenotype.Bi-allelic pathogenic variants in any one of many genes can cause autosomal recessive RP (ARRP).Where ARRP arises from variants in rod phototransduction genes (in contrast to other genes), one hallmark is early onset nyctalopia since rod phototransduction is affected from birth, well before the onset of widespread rod photoreceptor degeneration [1].When the latter occurs, consequent cone death in the peripheral retina leads to visual field loss.Loss of central visual acuity (VA) can occur at advanced stages when foveal cones degenerate.Here, we compared visual acuities in ARRP associated with variants in four genes: PDE6A and PDE6B encode alpha and beta subunits of rod phosphodiesterase (PDE), which, when activated in phototransduction, hydrolyzes cyclic GMP; CNGA1 and CNGB1 encode alpha and beta subunits of the rod cyclic nucleotidegated (CNG) outer segment cation channels, which allow entry of sodium and calcium ions, and which close in response to the PDE-mediated reduction in cyclic GMP.We hypothesized that the two mechanisms might lead to differing RP progression rates, which might be detectable as differences in age-adjusted VA levels.We hypothesized that with PDE dysfunction, intracellular calcium levels might be higher (CNG channels remain open due to high cyclic GMP), possibly predisposing to faster degeneration; with CNG channel impairment, by comparison, intracellular calcium levels would be likely lower (due to restricted entry).