April 2009
Volume 50, Issue 13
ARVO Annual Meeting Abstract  |   April 2009
Functional Analysis of Disease-Causing NR2E3 Mutations
Author Affiliations & Notes
  • P. Escher
    IRO-Inst. for Res. in Ophthalmology, Sion, Valais, Switzerland
  • N. Voirol
    IRO-Inst. for Res. in Ophthalmology, Sion, Valais, Switzerland
  • T. Favez
    IRO-Inst. for Res. in Ophthalmology, Sion, Valais, Switzerland
  • R. Roduit
    IRO-Inst. for Res. in Ophthalmology, Sion, Valais, Switzerland
  • D. F. Schorderet
    IRO-Inst. for Res. in Ophthalmology, Sion, Valais, Switzerland
    EPFL-Ecole Polytechnique Fédérale, Lausanne, Switzerland
  • Footnotes
    Commercial Relationships  P. Escher, None; N. Voirol, None; T. Favez, None; R. Roduit, None; D.F. Schorderet, None.
  • Footnotes
    Support  Swiss NF Grant 31-122269
Investigative Ophthalmology & Visual Science April 2009, Vol.50, 2296. doi:
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      P. Escher, N. Voirol, T. Favez, R. Roduit, D. F. Schorderet; Functional Analysis of Disease-Causing NR2E3 Mutations. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2296.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : We analyzed the transcriptional activity of disease-causing NR2E3 mutant proteins in a heterologous system. NR2E3 belongs to the nuclear receptor superfamily of transcription factors, characterized by evolutionary-conserved DNA-binding (DBD) and ligand-binding (LBD) domains. NR2E3 acts in concert with the transcription factors CRX and NRL to repress cone-specific genes and activate rod-specific genes in rod photoreceptors. During development, NR2E3 is also required to suppress cone cell generation from retinal progenitor cells. In humans, mutations in NR2E3 have been associated with the recessively inherited enhanced short wavelength sensitive (S-) cone syndrome (ESCS), the Goldman-Favre syndrome, and, more recently, with autosomal dominant retinitis pigmentosa (adRP).

Methods: : The different NR2E3 mutants were generated by QuickChangeR mutagenesis and analyzed by transfection in heterologous HEK293T cells.

Results: : In transactivation assays in HEK293T cells, the adRP-linked p.G56R mutant protein exhibited a more severe effect both in activation of a rhodopsin promoter reporter construct and in repression of M-opsin promoter reporter construct, than the ESCS-linked R76Q, R76W, G88V, R97H, R104Q, R104W mutants of the DBD. In contrast, the ESCS-linked p.R311Q mutant of the LBD behaved like the NR2E3 wild-type protein in these assays. By co-expressing the corepressors atrophin-1 and -2, a differential repression of the M-opsin promoter was observed in presence of the p.R311Q, p.R385P and p.M407K. Interestingly, corepressor expression also affected the activity of CRX, but not NRL, in both rhodopsin and M-opsin transactivation assays.

Conclusions: : Taken together, these in vitro results suggest a distinct disease mechanism for the adRP-linked mutation, but open the possibility of different mechanisms for the development of ESCS that is clinically characterized by important phenotypic variations.

Keywords: transgenics/knock-outs • photoreceptors • mutations 

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