Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate

Hereditary human retinal degenerative diseases usually affect the mature ph otoreceptor topography by reducing the number of cells through apoptosis, r esulting in loss of visual function(1). Only one inherited retinal disease, the enhanced S-cone syndrome (ESCS), manifests a gain in function of photo receptors. ESCS is an autosomal recessive retinopathy in which patients hav e an increased sensitivity to blue light; perception of blue light is media ted by what is normally the least populous cone photoreceptor subtype, the S (short wavelength, blue) cones(2-8). People with ESCS also suffer visual loss, with night blindness occurring from early in life, varying degrees of L (long, red)- and M (middle, green)-cone vision, and retinal degeneration . The altered ratio of S- to L/M-cone photoreceptor sensitivity in ESCS may be due to abnormal cone cell fate determination during retinal development (7). In 94% of a cohort of ESCS probands we found mutations in NR2E3 (also known as PNR), which encodes a retinal nuclear receptor recently discovered to be a ligand-dependent transcription factor(9). Expression of NR2E3 was limited to the outer nuclear layer of the human retina. Our results suggest that NR2E3 has a role in determining photoreceptor phenotype during human retinogenesis.