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Mutations in NR2E3 can cause dominant or recessive retinal degenerations in the same family

Authors

  • Pascal Escher,

    1. Institut de Recherche en Ophtalmologie (IRO), Sion, Switzerland
    2. Department of Ophthalmology, University of Lausanne, Lausanne, Switzerland
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    • Pascal Escher and Peter Gouras contributed equally to this work.

  • Peter Gouras,

    1. Department of Ophthalmology, Columbia University, New York, New York
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    • Pascal Escher and Peter Gouras contributed equally to this work.

  • Raphaël Roduit,

    1. Institut de Recherche en Ophtalmologie (IRO), Sion, Switzerland
    2. Department of Ophthalmology, University of Lausanne, Lausanne, Switzerland
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  • Leila Tiab,

    1. Institut de Recherche en Ophtalmologie (IRO), Sion, Switzerland
    2. Department of Ophthalmology, University of Lausanne, Lausanne, Switzerland
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  • Sylvain Bolay,

    1. Institut de Recherche en Ophtalmologie (IRO), Sion, Switzerland
    2. Department of Ophthalmology, University of Lausanne, Lausanne, Switzerland
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  • Tania Delarive,

    1. Institut de Recherche en Ophtalmologie (IRO), Sion, Switzerland
    2. Department of Ophthalmology, University of Lausanne, Lausanne, Switzerland
    3. Hôpital Ophtalmique Jules-Gonin, Lausanne, Switzerland
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  • Shiming Chen,

    1. Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri
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  • Chih-Cheng Tsai,

    1. Department of Physiology and Biophysics, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey
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  • Masanori Hayashi,

    1. Department of Ophthalmology, Columbia University, New York, New York
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  • Jana Zernant,

    1. Department of Ophthalmology, Columbia University, New York, New York
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  • Joanna E. Merriam,

    1. Department of Ophthalmology, Columbia University, New York, New York
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  • Nicolas Mermod,

    1. Laboratory of Molecular Biotechnology, Center for Biotechnology, Ecole Polytechnique Fédérale de Lausanne–University of Lausanne (EPFL-UNIL), Lausanne, Switzerland
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  • Rando Allikmets,

    1. Departments of Ophthalmology and Pathology and Cell Biology, Columbia University, New York, New York
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  • Francis L. Munier,

    1. Department of Ophthalmology, University of Lausanne, Lausanne, Switzerland
    2. Hôpital Ophtalmique Jules-Gonin, Lausanne, Switzerland
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  • Daniel F. Schorderet

    Corresponding author
    1. Institut de Recherche en Ophtalmologie (IRO), Sion, Switzerland
    2. Department of Ophthalmology, University of Lausanne, Lausanne, Switzerland
    3. EPFL, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
    • Institut de Recherche en Ophtalmologie, Av. du Grand-Champsec 64, CH-1950 Sion, Switzerland
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  • Communicated by Andreas Gal

Abstract

NR2E3, a photoreceptor-specific nuclear receptor (PNR), represses cone-specific genes and activates several rod-specific genes. In humans, mutations in NR2E3 have been associated with the recessively-inherited enhanced short-wavelength sensitive S-cone syndrome (ESCS) and, recently, with autosomal dominant (ad) retinitis pigmentosa (RP) (adRP). In the present work, we describe two additional families affected by adRP that carry a heterozygous c.166G>A (p.G56R) mutation in the NR2E3 gene. Functional analysis determined the dominant negative activity of the p.G56R mutant protein as the molecular mechanism of adRP. Interestingly, in one pedigree, the most common causal variant for ESCS (p.R311Q) cosegregated with the adRP-linked p.G56R mutation, and the compound heterozygotes exhibited an ESCS-like phenotype, which in 1 of the 2 cases was strikingly “milder” than the patients carrying the p.G56R mutation alone. Impaired repression of cone-specific genes by the corepressors atrophin-1 (dentatorubral-pallidoluysian atrophy [DRPLA] gene product) and atrophin-2 (arginine-glutamic acid dipeptide repeat [RERE] protein) appeared to be a molecular mechanism mediating the beneficial effect of the p.R311Q mutation. Finally, the functional dominance of the p.R311Q variant to the p.G56R mutation is discussed. Hum Mutat 0,1–10, 2008. © 2008 Wiley-Liss, Inc.

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