NR2E3mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP)

Abstract

NR2E3, also called photoreceptor-specific nuclear receptor (PNR), is a transcription factor of the nuclear hormone receptor superfamily whose expression is uniquely restricted to photoreceptors. There, its physiological activity is essential for proper rod and cone photoreceptor development and maintenance. Thirtytwo different mutations in NR2E3 have been identified in either homozygous or compound heterozygous state in the recessively inherited enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), and clumped pigmentary retinal degeneration (CPRD). The clinical phenotype common to all these patients is night blindness, rudimental or absent rod function, and hyperfunction of the ''blue'' S-cones. A single p.G56R mutation is inherited in a dominant manner and causes retinitis pigmentosa (RP). We have established a new locus-specific database for NR2E3 (www.LOVD.nl/eye), containing all reported mutations, polymorphisms, and unclassified sequence variants, including novel ones. A high proportion of mutations are located in the evolutionarily-conserved DNA-binding domains (DBDs) and ligand-binding domains (LBDs) of NR2E3. Based on homology modeling of these NR2E3 domains, we propose a structural localization of mutated residues. The high variability of clinical phenotypes observed in patients affected by NR2E3-linked retinal degenerations may be caused by different disease mechanisms, including absence of DNA-binding, altered interactions with transcriptional coregulators, and differential activity of modifier genes.

Homozygosity for a Recessive Loss-of-Function Mutation of the NRL Gene Is Associated With a Variant of Enhanced S-Cone Syndrome

“…3-6) that included the following: (1) rod ERG was undetectable in the dark-adapted state; (2) the photopic and scotopic responses to the same white light stimulus had similar delayed waveform; (3) the amplitude of the photopic ISCEV standard 26 30-Hz flicker was smaller than that of the a-wave in the single flash photopic ERG (ISCEV standard 26 ); (4) the photopic b-wave of the transient responses to bright white stimuli was prolonged, and increased in amplitude with increasing stimulus energy, in contrast to the ''photopic hill'' behavior in volunteers with normal photopic ERG; (5) shortwavelength cone (S-cone) ERG responses had delayed implicit times and larger a-wave amplitudes than those of normal subjects; and (6) function of L-and M-cones was significantly reduced. These ERG characteristics are very similar to those reported for ESCS patients, [9][10][11][12]14,16 suggesting that patients A-1 and B-1 represent a variant of ESCS.…”

“…8,9 Electroretinography (ERG) shows no rod function, depressed function of M-and L-cones, and enhanced S-cone function, leading to the diagnosis of enhanced S-cone syndrome (ESCS). [10][11][12] A histologic report of a patient with ESCS supports the ERG-based diagnosis, showing a degenerate retina with no rods and twice the usual number of cones, most of which express the short-wavelength opsin. 13 A variety of fundus appearances have been described in ESCS, the most typical being nummular pigmentary deposition at the level of the retinal pigment epithelium (RPE), usually outside the vascular arcades.…”

“…3, third column) of A-1, B-1, and the ESCS patients were delayed and markedly subnormal, smaller than the a-wave amplitude of the light-adapted ERG response to 3.0 cd-s/m 2 , which is a typical finding in ESCS patients. [9][10][11][12] The isolated rod response (Fig. 3, fourth column), elicited by a dim blue stimulus in the dark-adapted state, was nonrecordable in A-1, B-1, and ESCS patients.…”

Double Concentric Autofluorescence Ring inNR2E3-p.G56R-Linked Autosomal Dominant Retinitis Pigmentosa

“…8 The 33 recessive and one dominant mutation identified so far in the NR2E3 gene have been listed in a public database at www.lovd.nl/eye. 9 Recessive mutations in NR2E3 caused Goldmann-Favre syndrome (GFS), also called enhanced short wavelength (S-) cone sensitivity syndrome (ESCS: enhanced Scone syndrome; MIM# 268100). 10,11 Initial diagnosis of a substantial number of patients was clumped pigmentary retinal degeneration (CPRD) or autosomal recessive RP (ARRP).…”

“…On fundus photography, a mid-peripheral RPE atrophy with nummular pigment deposits along the vascular arcades was a characteristic clinical sign. 9,14,15 The proliferation of S-cones was detected by spectral ERG as a pathognomonic hyperfunction in response to blue light. 16 Intriguingly, a unique dominantly inherited c.166G > A (p.G56R) mutation located in the DNA-binding domain (DBD) of NR2E3 caused ADRP (MIM# 611131]).…”