Recurrent Mutation in the First Zinc Finger of the Orphan Nuclear Receptor NR2E3 Causes Autosomal Dominant Retinitis Pigmentosa

• Published in: American journal of human genetics 2007-07, Vol.81 (1), p.147-157
• Main Authors: Coppieters, Frauke, Leroy, Bart P., Beysen, Diane, Hellemans, Jan, De Bosscher, Karolien, Haegeman, Guy, Robberecht, Kirsten, Wuyts, Wim, Coucke, Paul J., De Baere, Elfride
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Belgium; Biological and medical sciences; Cells; Chromosome Mapping; Female; Fundamental and applied biological sciences. Psychology; Gene loci; General aspects. Genetic counseling; Genes, Dominant; Genetic disorders; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Heterozygote; Humans; Male; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Mutation; Mutation, Missense; Ophthalmology; Orphan Nuclear Receptors; Pedigree; Receptors, Cytoplasmic and Nuclear - chemistry; Receptors, Cytoplasmic and Nuclear - genetics; Retina; Retinitis Pigmentosa - genetics; Retinitis Pigmentosa - pathology; Retinopathies; Transcription Factors - chemistry; Transcription Factors - genetics; Zinc Fingers - genetics
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/518426

“Autosomal dominant retinitis pigmentosa” (adRP) refers to a genetically heterogeneous group of retinal dystrophies, in which 54% of all cases can be attributed to 17 disease loci. Here, we describe the localization and identification of the photoreceptor cell-specific nuclear receptor gene NR2E3 as a novel disease locus and gene for adRP. A heterozygous mutation c.166G→A (p.Gly56Arg) was identified in the first zinc finger of NR2E3 in a large Belgian family affected with adRP. Overall, this missense mutation was found in 3 families affected with adRP among 87 unrelated families with potentially dominant retinal dystrophies (3.4%), of which 47 were affected with RP (6.4%). Interestingly, affected members of these families display a novel recognizable NR2E3-related clinical subtype of adRP. Other mutations of NR2E3 have previously been shown to cause autosomal recessive enhanced S-cone syndrome, a specific retinal phenotype. We propose a different pathogenetic mechanism for these distinct dominant and recessive phenotypes, which may be attributed to the dual key role of NR2E3 in the regulation of photoreceptor-specific genes during rod development and maintenance.