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L. Bouayed–Tiab, T. Delarive, C. Agosti, F.–X. Borruat, F.L. Munier, D.F. Schorderet; A Heterozygous Mutation in the NR2E3 Gene Is Associated With an Autosomal Dominant Retinitis Pigmentosa . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1033.
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© ARVO (1962-2015); The Authors (2016-present)
To map a locus and identify the gene causing an autosomal dominant retinitis pigmentosa in a large Swiss family
Complete ophthalmic examination was performed in a large 4–generation family from Switzerland affected with autosomal retinitis pigmentosa, including best corrected visual acuity, full field ERG, Goldmann kinetic perimetry and fundus photography. Blood samples were collected from 11 out of 13 affected and 16 out of 18 non–affected members after informed consent. A genome–wide linkage analysis using dinucleotide microsatellite markers was done and lod scores were calculated with MLINK using equal allele frequency and a new mutation rate of 10–4. Each exon of the NR2E3 gene was amplified from genomic DNA and screened by DHPLC. Amplicons with abnormal retention times were directly sequenced.
First symptom was nyctalopia followed by photophobia and visual loss. Visual field showed concentric loss of sensibility. Clumped pigmented peripheral retinopathy was observed in all patients. Bull's eye–like maculopathy which progressed to diffuse chorioretinal atrophy of the posterior pole was observed in the 2 oldest patients. Visual acuity was highly variable. Among 6 patients with ERG, 2 had flat recordings, while 4 showed a moderate loss of scotopic function with normal photopic response. Linkage and haplotype analyses in this family placed the locus in a 16–cM interval between markers D15S153 and D15S205. A positive lod score of 3.60 at theta = 0.04 was obtained for D15S131. NR2E3, a locus for a recessive RP, mapped to this chromosomal region. Mutation analysis revealed a missense mutation in exon 2 (c.356G>A, p.G56R) in all affected members. This nucleotide substitution was not observed in 100 individual controls
Mutations in NR2E3 are responsible for the autosomal recessive enhanced S–cone syndrome (ESCS), a syndrome characterized by an increased sensitivity to blue light, visual loss with night blindness occurring early in life and retinal degeneration. Patients from our family show clear dominant inheritance, with male–to–male transmission. Pseudo–dominance can be ruled out as ESCS is rather rare. It is likely that different mutations in NR2E3 may cause various phenotypes, the classical recessive ESCS and this newly described dominant RP. This may not represent a unique situation and the mode of transmission should be used with caution when excluding candidate genes
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