Novel p.M96T variant of NRL and shRNA-based suppression and replacement of NRL mutants associated with autosomal dominant retinitis pigmentosa
Version of Record online: 2 NOV 2011
© 2011 John Wiley & Sons A/S
Volume 82, Issue 5, pages 446–452, November 2012
How to Cite
Hernan, I., Gamundi, M., Borràs, E., Maseras, M., García-Sandoval, B., Blanco-Kelly, F., Ayuso, C. and Carballo, M. (2012), Novel p.M96T variant of NRL and shRNA-based suppression and replacement of NRL mutants associated with autosomal dominant retinitis pigmentosa. Clinical Genetics, 82: 446–452. doi: 10.1111/j.1399-0004.2011.01796.x
- Issue online: 10 OCT 2012
- Version of Record online: 2 NOV 2011
- Accepted manuscript online: 7 OCT 2011 03:33PM EST
- Received 27 July 2011, revised and accepted for publication 4 October 2011
- autosomal dominant retinitis pigmentosa;
- NRL gene;
- RNA interference;
- suppression and replacement
Hernan I, Gamundi MJ, Borràs E, Maseras M, García-Sandoval B, Blanco-Kelly F, Ayuso C, Carballo M. Novel p.M96T variant of NRL and shRNA-based suppression and replacement of NRL mutants associated with autosomal dominant retinitis pigmentosa.
Mutations in the gene encoding the transcription factor neural retina leucine zipper (NRL) are known to cause autosomal dominant (adRP) or recessive (arRP) retinitis pigmentosa (RP). In an adRP Spanish family, we detected a novel sequence variation (c.287T>C) in the NRL gene that results in the p.M96T protein change. A functional test of the ability of NRL, in conjunction with cone-rod homeobox (CRX), to transactivate a human rhodopsin (RHO) promoter was used to evaluate the pathogenic mechanisms of NRL. We found upregulation of the RHO promoter by p.M96T protein similar to that shown by other missense NRL mutations that cause adRP. Affected RP patients of the family carry the nucleotide change, although two other family members that also carry the c.287T>C variation remain asymptomatic. This result complicates the genetic counselling of the family.
The pathogenic mechanisms associated with adRP NRL mutations appear to be caused by a gain of function. To suppress the negative effect of an NRL mutant, the suppression and replacement strategy seems to be the most suitable therapeutic approach capable of overcoming the mutational heterogeneity associated with NRL-linked adRP. Thus, we evaluated this methodology in the NRL gene for the first time.