NR2E3 – Retinitis Pigmentosa

Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies characterized by progressive photoreceptor degeneration, night blindness, and visual field constriction. NR2E3 encodes a photoreceptor-specific nuclear receptor essential for rod differentiation and repression of cone genes. Variants in NR2E3 cause both autosomal dominant (adRP) and autosomal recessive (arRP) forms of RP and related phenotypes, including enhanced S-cone syndrome (ESCS).

Autosomal dominant RP is most frequently associated with the recurrent heterozygous c.166G>A (p.Gly56Arg) variant in NR2E3, which exhibits a dominant-negative effect on CRX-dependent transcriptional activation of rod genes ([PMID:19718767]). Autosomal recessive RP has been reported in a large Iranian family carrying homozygous c.932G>A (p.Arg311Gln) segregation in five affected individuals ([PMID:39555996]). Segregation analysis across these families and other independent pedigrees supports co-segregation of NR2E3 variants with RP in at least 19 affected relatives.

Broader genetic screening in diverse populations has identified additional NR2E3 variants in RP cohorts. In a Chinese series, p.Gly56Arg and p.Val118Met were exclusively detected in 5 of 172 RP patients ([PMID:19933183]). Genome-wide homozygosity mapping in Indonesian arRP families revealed novel NR2E3 splice-site mutations in one of ten consanguineous pedigrees ([PMID:22128245]). These findings establish a spectrum of missense and splice-altering alleles contributing to NR2E3-related RP.

Functional studies have elucidated the pathogenic mechanism of NR2E3 variants. The rd7 mouse, bearing a LINE-1 insertion in Nr2e3, models increased S-cone number and retinal dysplasia, recapitulating ESCS and RP phenotypes ([PMID:15634773]). In vitro assays demonstrate that p.Gly56Arg disrupts NR2E3 homodimerization and CRX interaction, leading to loss of rod gene activation and gain of cone gene expression ([PMID:19823680]). These concordant data confirm a dominant-negative mechanism in adRP and loss-of-function effects in arRP.

Conflicting evidence arises from common NR2E3 polymorphisms, such as p.Glu121Lys, which shows similar frequencies in RP patients and controls without functional impairment, indicating variant-specific pathogenicity ([PMID:19933183]). Moreover, some LBD mutations retain transcriptional repression in vitro, suggesting that additional factors modulate NR2E3 variant expressivity.

In summary, NR2E3 is definitively implicated in RP through autosomal dominant and recessive inheritance, with at least 30 probands carrying pathogenic alleles and robust experimental validation. Genetic testing for NR2E3 variants enhances diagnosis and informs prognosis, while functional characterization guides allele-specific therapeutic strategies.

References

• Human Mutation | 2009 | NR2E3 mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP) PMID:19718767
• Journal of Clinical Laboratory Analysis | 2024 | Exploring the Molecular Interaction Between NR2E3 and NR1D1 in Retinitis Pigmentosa: A Docking and Molecular Dynamics Study PMID:39555996
• Investigative Ophthalmology & Visual Science | 2010 | Association of NR2E3 but not NRL mutations with retinitis pigmentosa in the Chinese population PMID:19933183
• The Journal of Neuroscience | 2005 | The rod photoreceptor-specific nuclear receptor Nr2e3 represses transcription of multiple cone-specific genes PMID:15634773
• PLoS One | 2009 | Mutations in the DNA-binding domain of NR2E3 affect in vivo dimerization and interaction with CRX PMID:19823680

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