Novel Pathogenic Sequence Variants in NR2E3 and Clinical Findings in Three Patients

Abstract

A retrospective review of the clinical records of patients seen at the Oxford Eye Hospital identified as having NR2E3 mutations was performed. The data included symptoms, best-corrected visual acuity, multimodal retinal imaging, visual fields and electrophysiology testing. Three participants were identified with biallelic NR2E3 pathogenic sequence variants detected using a targeted NGS gene panel, two of which were novel. Participant I was a Nepalese male aged 68 years, and participants II and III were white Caucasian females aged 69 and 10 years old, respectively. All three had childhood onset nyctalopia, a progressive decrease in central vision, and visual field loss. Patients I and III had photopsia, patient II had photosensitivity and patient III also had photophobia. Visual acuities in patients I and II were preserved even into the seventh decade, with the worst visual acuity measured at 6/36. Visual field constriction was severe in participant I, less so in II, and fields were full to bright targets targets in participant III. Electrophysiology testing in all three demonstrated loss of rod function. The three patients share some of the typical distinctive features of NR2E3 retinopathies, as well as a novel clinical observation of foveal ellipsoid thickening.

Next-Generation Sequencing Applications for Inherited Retinal Diseases

“…WES exclusively captures the protein-coding exons, but only accounts for approximately 1% of the genome. It is important to note that exon-based sequencing is likely to also reliably detect intronic variants located close to the targeted exons, such as non-canonical splice site variants, which are known causes of IRDs [ 28 , 29 , 30 ]. WGS is significantly more comprehensive including introns, promoters, and intergenic regions; in principle sequencing every nucleotide possible in a sample.…”

Regulation of the stem‑like properties of estrogen receptor‑positive breast cancer cells through NR2E3/NR2C2 signaling

“…In retinal cells, NR2E3 mediates the expression of photoreceptor genes such as rhodopsin and gnat1 on the transcriptional level ( 29 ). In tumor cells, NR2E3 can function as an epigenetic modulator to regulate the chromatin accessibility of target genes, such as esr1 , aryl hydrocarbon receptor and long non-coding RNA damage-induced noncoding ( 3 , 9 , 30 ).…”

Genetic dissection of non-syndromic retinitis pigmentosa

“…Retinal diseases caused by this gene include ADRP, ARRP, enhanced S-cone syndrome, goldmann–favre syndrome and clumped pigmentary retinal degeneration. [ 71 ]…”

“…The gene encodes for a protein of 45 kDa with 410 amino acid residues which is a photoreceptor specific transcription factor which plays crucial role in rod cells development and maintenance. [ 71 ] It promotes rod-specific genes (e.g., RHO) transcription and represses the cone-specific genes by associating with other genes including CRX , NRL and NR1D1 . It has the structure of nuclear receptor and involves N-terminal A/B domain (highly variable), C-domain (highly conserved and forms DBD), D-domain (most flexible and also called as hinge domain), and C-terminal E/F domain (conserved secondary structure, also called as LBD).…”