Pascal Escher and Peter Gouras contributed equally to this work.
Mutations in NR2E3 can cause dominant or recessive retinal degenerations in the same family†
Article first published online: 12 NOV 2008
© 2008 Wiley-Liss, Inc.
Volume 30, Issue 3, pages 342–351, March 2009
How to Cite
Escher, P., Gouras, P., Roduit, R., Tiab, L., Bolay, S., Delarive, T., Chen, S., Tsai, C.-C., Hayashi, M., Zernant, J., Merriam, J. E., Mermod, N., Allikmets, R., Munier, F. L. and Schorderet, D. F. (2009), Mutations in NR2E3 can cause dominant or recessive retinal degenerations in the same family. Hum. Mutat., 30: 342–351. doi: 10.1002/humu.20858
Communicated by Andreas Gal
- Issue published online: 24 FEB 2009
- Article first published online: 12 NOV 2008
- Manuscript Accepted: 5 JUN 2008
- Manuscript Received: 28 NOV 2007
- Research to Prevent Blindness, Inc., New York, NY
- National Institutes of Health (NIH). Grant Numbers: EY015293, EY13435, EY12543
- Swiss National Science Foundation. Grant Number: 31-111948
- retinal degeneration;
- transcriptional regulation;
- cofactor assembly;
- corepressor binding;
- photoreceptor-specific nuclear receptor;
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.