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F. Coppieters, E. Héon, I. Cima, D. Glavac, M. Hawlina, E. Mersy, S. Hooghe, B. P. Leroy, E. De Baere; Exploring the Role of Genes of the Retinal Transcription Network in Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3745.
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The photoreceptor cell-specific nuclear receptor gene NR2E3 is a key player in the retinal transcription network, with a dual regulatory role in the differentiation of the rod photoreceptors. NR2E3 is associated with autosomal dominant retinitis pigmentosa (RP) as well as with autosomal recessive enhanced S-cone syndrome (ESCS). The purpose of this study was to determine the contribution of NR2E3 in a population of 48 probands with retinal degeneration, including a subtype of RP and ESCS. A second purpose was to explore the involvement of other genes of the retinal transcription network: NRL and NR1D1 which both cooperate with NR2E3, and RDS, recently shown to be a direct target of NR2E3.
Belgian, Canadian, Slovenian and Croatian probands from 48 families with various retinal diseases were recruited after clinical evaluation. Direct sequencing was performed of the coding exons and intron-exon boundaries of NR2E3, NRL, NR1D1 and RDS.
We found 9 different NR2E3 mutations in 14/48 probands, of which 3 were novel. The most common mutation was c.119-2A>C, with a disease allele frequency of 5/23. Three probands were compound heterozygous for one mutation and one variant. Interestingly, one patient carried a complex allele c.[931C>T(+)932G>A]. In addition, a heterozygous c.378C>A (p.Ala63Asp) mutation was found in a proband with cone-rod dystrophy, of which the unaffected mother is also heterozygous for c.378C>A. Surprisingly, the maternal grandmother, who is offspring of first cousins, is homozygous for c.378C>A and displays an RP-like phenotype, thereby confirming the complex inheritance pattern of NR2E3 mutations. Probands in whom no NR2E3 mutations were found, underwent NRL, NR1D1 and RDS mutation screening. So far, no mutations were identified.
This study confirms the importance of NR2E3 in specific subtypes of retinal degeneration, as we demonstrated a mutational load of 29% of our patient population. NR1D1, NRL and RDS were not found to be associated with these phenotypes.
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