Loss of PILRB gene at age-related macular degeneration associated PILRB/PILRA locus impairs photoreceptor function in mouse retina

Genome-wide association studies have uncovered mostly non-coding variants at over 60 age- related macular degeneration (AMD) susceptibility loci. To ascertain the target gene at the PILRB/PILRA locus, we used a CRISPR strategy to produce germline deletions in the mouse paired immunoglobin-like type 2 receptor (Pilr) genes that encode highly related activating (PILRB) and inhibitory (PILRA) receptors. We show that a combined loss of Pilrb1 and Pilrb2, but not Pilra, leads to an early but relatively stationary defect in photoreceptor function without any apparent change in other retinal cells. PILRB immunostaining is specifically detected at the proximal part of photoreceptor outer segment. Reduced expression of select calcium-regulated phototransduction and synapse-associated proteins, including GCAP1 and 2, PDE6B, AIPL1, PSD95, and CTBP1, indicate dysregulation of calcium homeostasis as a possible mechanism of retinal phenotype in Pilrb1/2 -/- mice. Our studies suggest an association of PILRB, and not PILRA, with AMD pathogenesis.