Disruption of the Human Cone Photoreceptor Mosaic from a Defect in NR2E3 Transcription Factor Function

Abstract

 

Purpose

 

Enhanced S-cone syndrome is an orphan disease caused by mutations in the NR2E3 gene, which results in an increased number of S-cones overpopulating the retina. Although the characteristic onset of enhanced S-cone syndrome can be well documented by current ophthalmic imaging modalities, techniques such as spectral domain optical coherence tomography (SD-OCT) and scanning laser ophthalmoscopy (SLO) fail to provide sufficient details regarding the microstructure of photoreceptors in retinal diseases. Adaptive optics (AO) provides a unique opportunity to analyze the effects of genetic mutations on photoreceptors by compensating for aberrations in the human eye.

 

Methods

 

3 eyes of 3 patients with enhanced S-cone syndrome were studied by clinical examination, genetic screening, fundus autofluorescence (FAF) imaging, SD-OCT, and electroretinography (ERG). Cone mosaic imaging was accomplished by an AO-SLO equipped with a dual crystal on silicon spatial light modulator. Qualitative image analyses and genetic findings were investigated in each patient.

 

Results

 

The diagnosis was confirmed by ERG and genetic analysis. Two disease-causing mutations in the NR2E3 gene were identified on 2 study patients, as well as a novel mutation (202 A>G, S68G) in the third. Fundus photograph, FAF and SD-OCT found a rosette-like lesion within the mid-periphery along the vascular arcades of the retina. In all AO-SLO images, sparse distribution and asymmetric size of cone mosaic pattern were found within central retina. There were regions of dark space between groups of photoreceptors, distinguishable from shadowing and artifacts.

 

Conclusions

 

AO-SLO provided an in-depth window into the retina of enhanced S-cone syndrome patients beyond the ability of other current imaging modalities. Dark lesions within the central retina contain structurally dysfunctional cones, which account for retinal mosaic disorganization and may predispose affected areas to other abnormalities such as rosettes. AO-SLO can be an efficient diagnostic tool in clinics for examining cellular-level pathologies in various retinal dystrophies.

 

 

 

Keywords: 552 imaging methods (CT, FA, ICG, MRI, OCT, RTA, SLO, ultrasound) • 689 retina: distal (photoreceptors, horizontal cells, bipolar cells) • 494 degenerations/dystrophies