Shared Mutations in NR2E3 In Enhanced S-cone Syndrome, Goldmann-Favre Syndrome, and Clumped Pigmentary Retinal Degeneration

Abstract

Abstract: : Purpose: To test the hypothesis that mutations in the photoreceptor-specific nuclear receptor gene (PNR or NR2E3) cause enhanced S-cone syndrome (ESCS), Goldmann-Favre syndrome (GFS), and clumped pigmentary retinal degeneration (CPRD), and to investigate the clinical findings of patients with NR2E3 mutations. Methods: The NR2E3 coding regions and intron-exon boundaries were amplified by PCR from leukocyte DNA samples from one patient with ESCS, one patient with GFS, and 19 unrelated patients with CPRD. The PCR products were directly sequenced. We evaluated visual acuity, refractive error, visual fields, fundi, final dark-adaptation thresholds, and electroretinograms. Results: The patient with ESCS, the patient with GFS, and 8 of the 19 patients with CPRD had NR2E3 mutations. Six different mutations were found in these 10 patients, 2 of which were novel: a missense mutation (Ala256Glu) and a frameshift mutation (Pro276(del17 bp)), which is the first obviously null allele reported in this gene. Two patients were homozygotes (both with CPRD) and 8 had two distinct mutations that were presumably allelic or were proven to be so through segregation analysis. All but one of the mutations in the patients with ESCS and GFS were also found in patients with CPRD. All cases with NR2E3 mutations were hyperopes and had signs of a progressive retinal degeneration. Clumped pigment deposits in the retina were recognized also in the patients with the ESCS and GFS. Eleven patients with CPRD did not carry any NR2E3 mutations and their ocular findings were compared with those of patients with mutations. Patients with NR2E3 mutations were more frequently hyperopes (11/11 NR2E3 cases vs. 4/10 without mutations, p = 0.004). The NR2E3 cases had a higher average elevation of their final dark adaptation threshold (3.54 vs. 1.98 log units, p = 0.03). Conclusion: Most if not all cases of ESCS and GFS, and many cases of CPRD, have the same genetic basis. The hyperopic refractive error in these diseases is a newly recognized characteristic of NR2E3 disease. The absence of detected mutations in some patients with CPRD, and the low frequency of hyperopia in CPRD patients without NR2E3 detected mutations, suggest that one or more other genes may also cause this form of retinitis pigmentosa.

Keywords: 335 candidate gene analysis • 420 genetics • 562 retinal degenerations: hereditary