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 photoreceptor topography by reducing the number of cells through apoptosis, resulting in loss of visual function 1 . Only one inherited retinal disease, the enhanced S-cone syndrome (ESCS), manifests a gain in function of photoreceptors. ESCS is an autosomal recessive retinopathy in which patients have an increased sensitivity to blue light; perception of blue light is mediated by what is normally the least populous cone photoreceptor subtype, the S (short wavelength, blue) cones 2 , 3 , 4 , 5 , 6 , 7 , 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.