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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 function1. 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) cones2,3,4,5,6,7,8. 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 development7. 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 factor9. 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.

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We thank D. Nishimura for critical suggestions; G. Hageman and the Lions Eye Bank for the kind gift of the human tissue; A. Kanis and J. Fingert for ocular tissue collection and dissection, J.J.-C. Lin and R. Reiter for use of the in situ hybridization facility; the Blodi Ocular Pathology Laboratory for tissue processing and embedding; J. Ross for technical assistance with tissue sectioning, photography and computer imaging; and E. De Castro, J. Huang, D. Marks and T. Aleman for help with all the patient-related aspects of the study. V.C.S. is an associate investigator of the Howard Hughes Medical Institute. This work was supported in part by Public Health Service research grants (EY11298, EY05627, EY10539, EY10564 and EY10900), the Foundation Fighting Blindness, the Grousbeck Family Foundation, the Carver Charitable Trusts and the Horvitz Family Foundation.

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Correspondence to Val C. Sheffield.

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Figure 1: Phenotype of ESCS.
Figure 2: Chromatograms showing 11 of 12 mutations identified in ESCS probands.
Figure 3: Pedigrees of consanguineous kindreds with ESCS.
Figure 4: BLAST homology results depicting the protein similarity of human NR2E3 with other receptors in humans as well as other species: human NR2E3 (humNR2E3);
Figure 5: NR2E3 expression