Identification and characterization of rod-derived cone viability factor.

Retinitis pigmentosa is an untreatable, inherited retinal disease that leads to blindness. The disease initiates with the loss of night vision due to rod photoreceptor degeneration, followed by irreversible, progressive loss of cone photoreceptor. Cone loss is responsible for the main visual handicap, as cones are essential for day and high-acuity vision. Their loss is indirect, as most genes associated with retinitis pigmentosa are not expressed by these cells. We previously showed that factors secreted from rods are essential for cone viability. Here we identified one such trophic factor by expression cloning and named it rod-derived cone viability factor (RdCVF). RdCVF is a truncated thioredoxin-like protein specifically expressed by photoreceptors. The identification of this protein offers new treatment possibilities for retinitis pigmentosa.

The loss of transcriptional inhibition by the photoreceptor-cell specific nuclear receptor (NR2E3) is not a necessary cause of enhanced S-cone syndrome.

PURPOSE: To investigate functional consequence on photoreceptor-cell specific nuclear receptor (NR2E3) transcriptional activity of enhanced S-cone syndrome (ESCS) mutations localized in ligand binding domain (LBD). METHODS: Point mutations were introduced into the LBD of full length and Gal4 chimeric NR2E3 receptors and transcriptional activity was investigated by using transient co-transfection assay on corresponding luciferase reporters. Expression and DNA binding properties of transfected mutant and wild-type receptors were tested by Western blotting and gel shift assay. RESULTS: Our analysis show that two ESCS mutations, missense mutations R385P and M407K, abolished NR2E3 repressive activity in the context of full-length and Gal4 chimeric receptors, while W234S and R311Q mutants retained their repressive activity in both assays. All mutant receptors maintained their stability and DNA binding ability. CONCLUSIONS: These results showed that NR2E3 mutations localized in LBD induce ESCS disease without affecting inhibitory activity as recorded in vitro. This demonstrates the absence of correlation between transcriptional inhibition and ESCS phenotype. This analysis suggests that NR2E3 might have transcriptional activation properties not yet identified.