Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3): Role in Retinal Development and Disease

Abstract

NR2E3 is a nuclear hormone receptor gene required for the correct development of the retinal rod photoreceptors. Expression of NR2E3 protein in rod cell precursors suppresses cone-specific gene expression and, in concert with other transcription factors including NRL, activates the expression of rod-specific genes. Pathogenic variants involving NR2E3 cause a spectrum of retinopathies, including enhanced S-cone syndrome, Goldmann–Favre syndrome, retinitis pigmentosa, and clumped pigmentary retinal degeneration, with limited evidence of genotype–phenotype correlations. A common feature of NR2E3-related disease is an abnormally high number of cone photoreceptors that are sensitive to short wavelength light, the S-cones. This characteristic has been supported by mouse studies, which have also revealed that loss of Nr2e3 function causes photoreceptors to develop as cells that are intermediate between rods and cones. While there is currently no available cure for NR2E3-related retinopathies, there are a number of emerging therapeutic strategies under investigation, including the use of viral gene therapy and gene editing, that have shown promise for the future treatment of patients with NR2E3 variants and other inherited retinal diseases. This review provides a detailed overview of the current understanding of the role of NR2E3 in normal development and disease, and the associated clinical phenotypes, animal models, and therapeutic studies.

Posterior Polar Annular Choroidal Dystrophy: Genetic Insights and Differential Diagnosis in Inherited Retinal Diseases

“…NR2E3 is part of the nuclear receptor family, comprising 48 members, including endocrine and orphan receptors [21]. During the embryonic stages, both rod and cone cells originate from a shared precursor specific to photoreceptors [21,22]. The NR2E3 gene plays a pivotal role in guiding the differentiation toward the rod cells rather than the cones.…”

“…The NR2E3 gene plays a pivotal role in guiding the differentiation toward the rod cells rather than the cones. Investigations involving both animal models and humans with NR2E3 mutations indicate that this gene has a dual function in photoreceptor differentiation: it inhibits the expression of genes associated with cones, e.g., OPNSW1 (encoding blue opsin), GNAT2, and the cone transducin subunits, while simultaneously facilitating the activation of genes specific to rods, including GNB1 (the rod transducin β subunit) and rhodopsin [21].…”

“…Transmembrane protein [48,49] Involved in photoreceptor disk morphogenesis [48,49] 4p15.32 [48,49] TIMP3 Metallopeptidase inhibitor [50] Involved in ocular development [50] 22q12.3 [50] CCD2D2A Binding domain protein [3] Uncertain significance, possibly related to cilia structure and function [3] 4q21.1 [3] CEP78 Centrosomal protein [51] May be involved in ciliary functions [51] 9q21.13 [51] NR2E3 Nuclear receptor [3,21,22,52] Key transcription factor for photoreceptor development [3,21,22,52] 15q23 [21,22] PCARE Ciliary and actin-associated protein [3,23,53] Probably associated with the primary cilium of the outer segment [3,23,53] 2p23.2 [53]…”

The Healthy and Diseased Retina Seen through Neuron–Glia Interactions

“…OCU400 (Ocugen Inc.) is a modifier gene therapy to treat people with inherited retinal diseases, retinitis pigmentosa, caused by a broad range of genetic mutations, and is currently in clinical trial phase 2. The therapeutic candidate is an adeno-associated virus serotype 5 (AAV5) containing the gene for the human nuclear hormone receptor NR2E3, and as a modifier gene therapy, it expands the patient reach, treating multiple mutations with a single product instead of developing a product for every mutation, and potentially decreasing costs [459]. This evolution signifies a shift towards more precise and personalized approaches, with the goal of not only treating symptoms but also addressing the root causes of complex diseases, ultimately paving the way for more effective and tailored therapeutic interventions.…”

Exonic splice variant discovery using in vitro models of inherited retinal disease

“…More than 80 pathogenic variants in NR2E3 have been described to date 8 . One of the more common ESCS-causing mutations in NR2E3 is a coding sequence variant at position 932 (NM_014249.4:c.932G>A), which converts codon 311 from C G G to C A G 1 .…”