NR2E3-Linked Retinal Degenerations: Enhanced S-Cone Sensitivity Syndrome, Goldmann-Favre Syndrome, Clumped Pigmentary Retinal Degeneration, and Retinitis Pigmentosa

3rd edition

NR2E3 (nuclear receptor, class 2, subfamily E, member 3; OMIM #604485) encodes the photoreceptor-specific nuclear receptor NR2E3/PNR. During the development of photoreceptors, this transcription factor has a dual function: it acts as a repressor of cone-specific gene expression in rod photoreceptors and as an activator of rhodopsin gene expression. Homozygous or compound heterozygous pathogenic variants in NR2E3 cause the recessively inherited enhanced S-cone syndrome (ESCS; OMIM #268100), also described as S-cone hypersensitivity syndrome, Goldmann-Favre syndrome (GFS) and clumped pigmentary retinal degeneration (CPRD). The misspecification of photoreceptor precursors in the absence of functional NR2E3 causes an increased number of S-cones and non-functional ‘hybrid’ rods expressing rod- and cone-specific genes, eventually resulting in “rosette-like” structures in the outer retina and night blindness. A unique heterozygous pathogenic NR2E3 c.166G>A (p.Gly56Arg/G56R) variant causes autosomal dominant retinitis pigmentosa (RP37; OMIM #611131).