NR2E3 is an orphan nuclear receptor transcription factor essential for rod photoreceptor development and function in the retina. 1 As a transcriptional activator, NR2E3 promotes rod-specific gene expression, including rhodopsin and rod phosphodiesterase, while simultaneously repressing cone-specific genes such as M- and S-opsin. 1 NR2E3 operates in concert with other transcription factors like NRL to establish proper photoreceptor identity during retinal development. 1 Loss of NR2E3 function causes rod precursor cells to misdifferentiate into cells with hybrid rod-cone characteristics or S-cone-like phenotypes, resulting in absent rod function and abnormally elevated short-wavelength light sensitivity. 2 Pathogenic NR2E3 variants cause a spectrum of inherited retinal dystrophies, primarily Enhanced S-cone Syndrome (ESCS), Retinitis Pigmentosa 37, and Goldmann-Favre syndrome. 1 3 ESCS is characterized by night blindness due to rod dysfunction, though early-stage visual acuity may remain relatively preserved. 2 Human organoid studies reveal that NR2E3 loss disrupts normal photoreceptor maturation and causes misexpression of cone-specific phototransduction genes in rods, with disease manifestations differing significantly from rodent models. 4 Progressive disease leads to characteristic retinal changes including macular schisis and periarcuate retinal degeneration. 5 6 Emerging therapeutic approaches, including gene therapy and gene editing, show promise for treating NR2E3-related retinopathies. 1