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B. P. Leroy, F. Coppieters, D. Beysen, J. Hellemans, K. Robbrecht, K. De Bosscher, G. Haegeman, W. Wuyts, P. Coucke, E. De Baere; Missense Mutations in the First Zinc Finger of the Orphan Nuclear Receptor NR2E3 Cause Autosomal Dominant Retinitis Pigmentosa or Cone-Rod Dystrophy. Invest. Ophthalmol. Vis. Sci. 2007;48(13):6001.
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© ARVO (1962-2015); The Authors (2016-present)
For autosomal dominant RP (ADRP) 17 disease loci have been mapped that account for 53.5% of all ADRP cases. Here, we describe the localization and identification of an additional causal disease gene for an ADRP phenotype in a four-generation Belgian family. Subsequent screening of a panel of 87 additional retinal dystrophy families was performed in order to seek extra evidence for causality.
Linkage-based candidate gene exclusion and genome-wide screening in four-generation family with ADRP. Screening of functional candidate genes by direct sequencing. Sequencing of NR2E3 in 87 families with potentially AD retinal dystrophies.
A novel ADRP locus of 16.52 cM on 15q21-15qter between D15S153 and D15S205 was identified. Refinement of the locus and candidate gene analysis led to the identification of a novel mutation c.356G>A (p.G56R) in exon 2 of the NR2E3 gene (MIM 604485), encoding the photoreceptor cell specific orphan nuclear receptor PNR, a key transcriptional regulator that controls photoreceptor differentiation and maintenance. Screening of the NR2E3 gene in other families with similar retinal phenotypes, identified this mutation in two additional families with ADRP. Haplotype analysis did not reveal a founder effect, and is thus suggestive of a mutation hotspot. These findings were obtained prior to the report of, and completely independently from the data reported in an ARVO2006 abstract (1033/B966) by L. Bouayed-Tiab and co-workers. In addition, a second novel mutation c.378C>A (p.A63D) was found in exon 2 of NR2E3 in a family with cone-rod dystrophy (CRD). Both missense mutations are located in the first zinc-finger of the DNA-binding domain (DBD) of NR2E3. Mutations in NR2E3 have previously been shown to cause autosomal recessive enhanced S-cone syndrome (ESCS), a distinct retinal phenotype.
Mutations in the first zinc-finger of the DBD of NR2E3 can cause ADRP or CRD. It is proposed that a different pathogenetic mechanism underlying the distinct dominant and recessive phenotypes may be attributed to the dual role of NR2E3 in the regulation of photoreceptor-specific genes. The findings further confirm the pathogenetic parallel between NR2E3 and NRL. Mutations in the latter can either lead to dominant or recessive phenotypes with striking similarity to either ESCS or the ADRP reported here.
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