Abstract
ImportanceThis research is the single largest NR2E3 genotype-phenotype correlation study performed to date in autosomal dominant Retinitis Pigmentosa.ObjectiveThe aim of this study is to analyse the frequency of the p.Gly56Arg mutation in NR2E3 for the largest cohort of autosomal dominant Retinitis Pigmentosa patients to date and its associated phenotype.Patients and MethodsA cohort of 201 unrelated Spanish families affected by autosomal dominant Retinitis Pigmentosa. The p.Gly56Arg mutation in the NR2E3 (NM_014249.2) gene was analysed in 201 families. In the 24 cases where the mutation had been detected, a haplotype analysis linked to the p.Gly56Arg families was performed, using four extragenic polymorphic markers D15S967, D15S1050, D15S204 and D15S188. Phenotype study included presence and age of onset of night blindness, visual field loss and cataracts; and an ophthalmoscopic examination after pupillary dilation and electroretinogram for the 24 cases.ResultsSeven of the 201 analyzed families were positive for the p.Gly56Arg, leading to a prevalence of 3.5%. Clinical data were available for 24 subjects. Night blindness was the first noticeable symptom (mean 15.9 years). Visual field loss onset was variable (23.3 ± 11.9 years). Loss of visual acuity appeared late in the disease´s evolution. Most of the patients with cataracts (50%) presented it from the third decade of life. Fundus changes showed inter and intrafamiliar variability, but most of the patients showed typical RP changes and it was common to find macular affectation (47.4%). Electroretinogram was impaired from the beginning of the disease. Two families shared a common haplotype. Additionally, all patients shared a 104Kb region between D15S1050 and the NR2E3 gene.ConclusionsThis study highlights the importance of p.Gly56Arg in the NR2E3 gene as a common mutation associated with adRP, and provides new clues to its phenotype, which can allow for a better clinical management and genetic counselling of patients and their families.
Highlights
Retinitis Pigmentosa (RP, MIM# 268000), with a prevalence of approximately one in 4000 [1], is the most common form of inherited retinopathy
This study highlights the importance of p.Gly56Arg in the NR2E3 gene as a common mutation associated with autosomal dominant form of RP (adRP), and provides new clues to its phenotype, which can allow for a better clinical management and genetic counselling of patients and their families
Our patients were classified as affected by RP according to the following clinical criteria: night blindness (NB), progressive loss of peripheral vision, fundus compatible with RP [3, 4], and pathologic electroretinogram (ERG) showing a marked reduction in rod or rod and cone signal [22]
Summary
The adRP diagnosis was based on pedigree data and ophthalmologic examination. Our patients were classified as affected by RP according to the following clinical criteria: night blindness (NB), progressive loss of peripheral vision (mid peripheral scotoma or ring scotoma), fundus compatible with RP [3, 4] (ophthalmoscopic examination after pupillary dilation), and pathologic electroretinogram (ERG) showing a marked reduction in rod or rod and cone signal (fullfield electroretinogram according to the standards of the International Society for Clinical Electrophysiology of Vision: http://www.iscev.org) [22]. Among 201 families, 60 had been studied previously, showing a negative result, using the first version of the adRP genotyping microarray, which did not include the p.Gly56Arg mutation [23]. Direct sequencing was used to analyse the 60 previously studied families, to confirm the results obtained with the genotyping microarray and to segregate the disease causative mutation p.Gly56Arg in the NR2E3 gene in the families. All ophthalmoscopic examination data available (19 patients) showed fundus alterations (Fig 2) These fundus alterations could be detected since the beginning of the vision impairment, visual acuity was not affected (Table 1). All available ERG recordings (scotopic, photopic and flicker) showed alterations from the beginning of the disease, and these changes could be detected around the first decade of life, when studied at that age (family RP-0711 patient IV:; and family RP-0030 patient III:6—Table 1 and S1 Fig).
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