* 604485

NUCLEAR RECEPTOR SUBFAMILY 2, GROUP E, MEMBER 3; NR2E3


Alternative titles; symbols

PHOTORECEPTOR-SPECIFIC NUCLEAR RECEPTOR; PNR


HGNC Approved Gene Symbol: NR2E3

Cytogenetic location: 15q23     Genomic coordinates (GRCh38): 15:71,810,554-71,818,253 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
15q23 Enhanced S-cone syndrome 268100 AR 3
Retinitis pigmentosa 37 611131 AD, AR 3

TEXT

Description

PNR, also known as NR2E3, encodes a retinal nuclear receptor that is a ligand-dependent transcription factor. The NR2E3 protein is part of a large family of nuclear receptor transcription factors involved in signaling pathways. Nuclear receptors have been shown to regulate pathways involved in embryonic development, as well as maintenance of proper cell function in adults. Members of this family are characterized by discrete domains that function in DNA and ligand binding.


Cloning and Expression

Kobayashi et al. (1999) identified a photoreceptor cell-specific nuclear receptor, designated PNR for 'photoreceptor-specific nuclear receptor,' that contains a unique proximal (P) box (CNGCSG) in the DNA-binding domain. By searching an EST database for vertebrate homologs of Drosophila 'tailless' (tll), Kobayashi et al. (1999) found a highly related partial human sequence that had been identified in an adult retina cDNA library. They obtained a full-length cDNA from a retinoblastoma cell line using RT-PCR and 3-prime RACE. Analysis of the 410-amino acid PNR sequence revealed a characteristic nuclear receptor structure, with a DNA-binding domain followed by a putative ligand-binding domain. The overall structure of PNR was most closely related to that of TLX (603849). In human cell lines, PNR expression was observed in retinoblastoma along with other photoreceptor marker genes such as CRX (602225). PNR was able to recognize a subset of TLX target sequences in vitro.

By Northern blot analysis, Haider et al. (2000) detected expression of a major 2.2-kb mature NR2E3 mRNA in normal human eye restricted to the neurosensory retina. By in situ hybridization, Haider et al. (2000) detected NR2E3 transcripts solely in the outer nuclear layer of the adult human neurosensory retina, where the nuclei of cone and rod photoreceptors reside.


Gene Structure

Kobayashi et al. (1999) determined that the PNR coding region contains 8 exons and spans 7 kb.


Gene Function

Cheng et al. (2004) reported that Nr2e3 expression was localized preferentially to the rod, and not to the cone, photoreceptor nuclei in rodent retina. Interaction with another orphan nuclear receptor, Nr1d1 (Rev-erb-alpha; 602408), was observed using multiple methods. In transient transfection studies, both Nr2e3 and Nr1d1 activated the promoters of rod phototransduction genes synergistically with neural retina leucine zipper (NRL; 162080) and cone-rod homeobox (CRX; 602225). All 4 proteins, Nr2e3, Nr1d1, Nrl, and Crx, could be coimmunoprecipitated from bovine retinal nuclear extracts, suggesting a multiprotein transcriptional regulatory complex. The authors suggested that NR2E3 may be involved in regulating the expression of rod photoreceptor-specific genes and may play a role in transcriptional regulatory network(s) during rod differentiation.

Using yeast 2-hybrid screens with Nr2e3 as bait, Peng et al. (2005) identified Crx as an interacting partner of Nr2e3. Immunoprecipitation assays confirmed the interaction and identified the DNA-binding domain of each protein as the interaction motif. Immunohistochemistry demonstrated that Crx and Nr2e3 were coexpressed by rod photoreceptors and their precursors. Chromatin immunoprecipitation assays on mouse retina demonstrated that Nr2e3 and Crx cooccupied the promoter/enhancer region of several rod and cone genes in the rod photoreceptor cells. The promoter/enhancer occupancy of Nr2e3 was Crx-dependent, suggesting that Nr2e3 may be associated with photoreceptor gene targets by interacting with Crx. Transient transfection assays demonstrated that Nr2e3 enhanced rhodopsin (180380), but repressed S- or M-cone opsin transcription when interacting with Crx. Quantitative real-time RT-PCR analysis on postnatal day 28 retina of the rd7 mouse revealed an upregulation of cone genes, but downregulation of rod genes. Several mutant forms of human NR2E3 identified from enhanced S-cone syndrome (ESCS; 268100) patients showed defects in interacting with Crx and/or in transcriptional regulatory function. Peng et al. (2005) suggested that NR2E3 may be a dual-function transcriptional regulator that acts in concert with CRX to promote and maintain the function of rod photoreceptors.


Mapping

Kobayashi et al. (1999) mapped the NR2E3 gene to 15q24 by fluorescence in situ hybridization. By radiation hybrid analysis and FISH, Rendtorff et al. (2000) mapped the NR2E3 gene to 15q22.3-q23. Haider et al. (2000) mapped the NR2E3 gene as part of their search for the chromosome 15-linked Bardet-Biedl syndrome gene. The NR2E3 genomic sequence was contained within a single BAC that resided between markers D15S131 and D15S204 on chromosome 15q23.


Molecular Genetics

Enhanced S-Cone Syndrome

Haider et al. (2000) analyzed NR2E3 sequence in families with Bardet-Biedl syndrome linked to chromosome 15 (BBS4; see 209900), as well as affected individuals from 50 additional BBS families with unknown linkage. They found no disease-causing mutations. They then screened a cohort of 400 patients with retinal degenerative disease, including a small subset of patients with enhanced S-cone syndrome (ESCS; 268100). They found plausible disease-causing NR2E3 mutations only in ESCS patients. A wider study of 35 individuals with ESCS, representing 3 consanguineous kindreds and 26 simplex families, including a set of monozygotic twins, revealed 12 different mutations in the NR2E3 gene. A mutation was found in NR2E3 in 94% of the patients.

The enhanced S-cone syndrome is the only inherited retinal disorder that shows increased visual function involving the minority S (blue) cones, and decreased rod and L/M (red/green) cone function. The disorder may result from abnormal cell-fate determination, leading to excess S cones at the expense of other photoreceptor subtypes. In 16 ESCS patients with the most common NR2E3 mutation, R311Q (604485.0005), Milam et al. (2002) documented an abnormal ratio of S- to L/M-cone function and progressive retinal degeneration. They studied the postmortem retina of an ESCS patient homozygous for the NR2E3 R311Q mutation. No rods were identified, but cones were increased approximately 2-fold, and 92% were S cones. Only 15% of the cones expressed L/M-cone opsin and some coexpressed S-cone opsin. The retina was disorganized, with densely packed cones intermixed with inner retinal neurons. The retina was also degenerate, retaining photoreceptors in only the central and far peripheral regions. These observations suggested a role for NR2E3 in regulation of human photoreceptor development. Degeneration of the NR2E3 retina may result from defective development, known S-cone fragility, or abnormal maintenance of mature photoreceptors.

Gerber et al. (2000) studied members of a highly consanguineous endogamous population of Crypto-Jews living in a mountainous area of Portugal with what may have been enhanced S-cone syndrome. Crypto-Jews are survivors of Spanish Jews who were persecuted in the late 15th century, escaped to Portugal, and were forced to convert to save their lives. By a genomewide search for homozygosity, Gerber et al. (2000) mapped the disease locus to 15q22-q24 in the region where the PNR gene is located. They identified homozygosity for the R311Q mutation in the NR2E3 gene, as the cause of the disorder in this population. Because of the closed nature of the population, Gerber et al. (2000) were not able to perform S-cone testing to confirm the diagnosis.

Goldmann-Favre Syndrome

In a 13-year-old boy with Goldmann-Favre syndrome (GFS; see 268100), a severe form of ESCS, Bernal et al. (2008) identified homozygosity for the R311Q mutation in the NR2E3 gene.

Retinitis Pigmentosa 37

Coppieters et al. (2007) identified a heterozygous missense mutation (G56R; 604485.0006) in the first zinc finger of the NR2E3 gene in a large Belgian family with autosomal dominant retinitis pigmentosa. Overall, this missense mutation was found in 3 families affected with adRP among 87 unrelated families with potentially dominant retinal dystrophies (3.4%), of which 47 were affected with RP (6.4%). Affected members of these families displayed a novel recognizable clinical subtype of adRP (611131). Other mutations of NR2E3 had been shown to cause autosomal recessive RP and enhanced S-cone syndrome (268100). Coppieters et al. (2007) proposed a different pathogenetic mechanism for these distinct dominant and recessive phenotypes, which may be attributable to the dual key role of NR2E3 in the regulation of photoreceptor-specific genes during rod development and maintenance.

Bernal et al. (2008) analyzed the NR2E3 gene in 96 patients with autosomal recessive retinitis pigmentosa, 3 patients with Goldmann-Favre syndrome (GFS), and 4 patients with retinoschisis who were negative for mutation in the XLRS1 gene (300839), and identified homozygosity for 3 different mutations in 1 patient with GFS and 5 with arRP (604485.0001, 604485.0005, and 604485.0007, respectively).

In a brother and sister with RP from a consanguineous southern Indian family, Kannabiran et al. (2012) identified homozygosity for a complex frameshift mutation in the NR2E3 gene (604485.0008).


Animal Model

The autosomal recessive retinal degeneration of the rd7 mouse was identified at the Jackson Laboratory. It causes retinal folding associated with retinal spots and late-onset retinal degeneration. Akhmedov et al. (2000) mapped the mutation to mouse chromosome 9 in a region homologous to human 15q23-q25. In studies of a pool of cDNAs generated by subtractive hybridization of mRNAs from normal and photoreceptorless rd mouse retinas (Bowes et al., 1989), Akhmedov et al. (2000) identified several photoreceptor-specific clones and mapped them to their chromosomal loci. One of these cDNAs, which corresponded to the PNR gene, mapped near the rd7 locus, making PNR a candidate gene. They identified a 380-nucleotide deletion in the coding region of the rd7 PNR message that created a frameshift and produced a premature stop codon. This deletion accounted for more than 32% of the normal protein and eliminated a portion of the DNA-binding domain. In addition, it may result in the rapid degradation of the rd7 PNR message by the nonsense-mediated decay pathway, preventing the synthesis of the corresponding protein. Their findings demonstrated that PNR expression is critical for the normal development and function of the photoreceptor cells.

Haider et al. (2001) determined that the rd7 phenotype results from a splicing error created by a genomic deletion of intron 4 and part of exon 4 in the Nr2e3 gene. Rd7 retinal tissue displayed whorls in the outer nuclear layer which were not apparent until postnatal day 12.5. The Nr2e3 message was abundant by postnatal day 2.5, prior to the development of S-cones. The data coincided with studies in humans showing that mutations in the Nr2e3 gene result in a unique type of retinal degeneration known as enhanced S-cone syndrome, where patients have a 30-fold increase in S-cone sensitivity compared to normal. Immunohistochemical staining of cone cells demonstrated that rd7 retinas have an increased number of cone cells compared to wildtype retinas. The authors proposed that Nr2e3 may function by regulating genes involved in cone cell proliferation, and mutations in this gene may lead to retinal dysplasia and degeneration by disrupting normal photoreceptor cell topography as well as cell-cell interactions.


ALLELIC VARIANTS ( 8 Selected Examples):

.0001 ENHANCED S-CONE SYNDROME

RETINITIS PIGMENTOSA 37, INCLUDED
NR2E3, IVS1AS, A-C
  
RCV000005864...

Enhanced S-Cone Syndrome

In 3 affected individuals of an extensive kindred with enhanced S-cone syndrome (ESCS; 268100), Haider et al. (2000) identified homozygosity for a splice acceptor site mutation, an A-to-C transversion in the splice acceptor site of intron 1 of the NR2E3 gene. Another distantly related affected family member was found to be heterozygous for the mutation, which was also identified in 8 simplex probands with ESCS. The mutation was not found in 500 control individuals.

Retinitis Pigmentosa 37

In a brother and sister with retinitis pigmentosa and hypopigmented clumped lesions in the posterior pole of both eyes (RP37; 611131), Bernal et al. (2008) identified homozygosity for the 119-2A-C splice acceptor mutation in intron 1 of the NR2E3 gene. Analysis of the RT-PCR products from the mRNA transcripts generated in transient expression studies showed that the mutation generated an aberrant splicing mechanism. The mutation was not found in 60 blood donor controls.


.0002 ENHANCED S-CONE SYNDROME

NR2E3, ARG76TRP
  
RCV000005866...

In 2 patients with enhanced S-cone syndrome (ESCS; 268100), Haider et al. (2000) identified a C-to-T transition in the NR2E3 gene, resulting in an arg76-to-trp substitution.


.0003 ENHANCED S-CONE SYNDROME

NR2E3, ARG76GLN
  
RCV000005867...

In a patient with enhanced S-cone syndrome (ESCS; 268100), Haider et al. (2000) identified an arg76-to-gln mutation resulting from a G-to-A transition in the NR2E3 gene.


.0004 ENHANCED S-CONE SYNDROME

NR2E3, 9-BP DEL
  
RCV000005868

In a patient with enhanced S-cone syndrome (ESCS; 268100), Haider et al. (2000) identified deletion of 9 bp of the NR2E3 gene, resulting in a 3-amino acid deletion (codons 67-69) in the NR2E3 protein.


.0005 ENHANCED S-CONE SYNDROME

GOLDMANN-FAVRE SYNDROME, INCLUDED
NR2E3, ARG311GLN
  
RCV000005869...

Enhanced S-Cone Syndrome

In Crypto-Jews (Marranos) in Portugal with what may have been enhanced S-cone syndrome (ESCS; 268100), Gerber et al. (2000) identified a 1020G-A transition in exon 6 of the NR2E3 gene, resulting in an arg311-to-gln (R311Q) substitution. Clinical evidence of retinitis pigmentosa started in the first decade with night blindness, followed during the second and third decades by a slow concentric reduction of the visual field. Visual acuity decreased around 40 years of age, but affected individuals were not completely blind even when elderly. The fundus showed typical features of RP, i.e., pigment deposits in the peripheral retina, retinal pigment epithelium atrophy, and waxy pallor of the optic nerve. Because of the closed nature of the population, Gerber et al. (2000) were not able to perform S-cone testing. They noted, however, that Haider et al. (2000) had identified the R311Q mutation in 13 of 29 unrelated patients (44.8%) who were thought to have enhanced S-cone syndrome.

Goldmann-Favre Syndrome

In a 13-year-old boy with Goldmann-Favre syndrome (GFS; see 268100), Bernal et al. (2008) identified homozygosity for the R311Q mutation in the NR2E3 gene. The mutation was not found in 60 blood donor controls.


.0006 RETINITIS PIGMENTOSA 37

NR2E3, GLY56ARG
  
RCV000005871...

In 3 families, 2 Belgian, 1 French, Coppieters et al. (2007) found that autosomal dominant retinitis pigmentosa (RP37; 611131) resulted from a 166G-A transition in exon 2 of the NR2E3 gene that caused a gly56-to-arg (G56R) amino acid substitution.


.0007 RETINITIS PIGMENTOSA 37

NR2E3, 5-BP DEL, NT1034
  
RCV000005872

In 2 sisters and their brother with retinitis pigmentosa (RP37; 611131), born of consanguineous parents, Bernal et al. (2008) identified homozygosity for a 5-bp deletion in exon 7 of the NR2E3 gene, predicted to generate a stop signal in codon 345 and result in a protein lacking part of the ligand-binding domain. Dilated funduscopic examination revealed minimal or no retinal vessel attenuation and the presence of clusters of large, clumped pigment deposits with vitreous floaters in the midperiphery of both eyes. The mutation was not found in 60 blood donor controls.


.0008 RETINITIS PIGMENTOSA 37

NR2E3, 2-BP DEL/25-BP INS, NT143
  
RCV000162027...

In a brother and sister from a consanguineous southern Indian family with retinitis pigmentosa mapping to chromosome 15 (RP37; 611131), Kannabiran et al. (2012) identified homozygosity for a 2-bp deletion and 25-bp insertion at codon 48 in exon 2 of the NR2E3 gene (c.143_144delGCins25), causing a frameshift predicted to result in a premature termination codon after 65 amino acids. The unaffected parents were heterozygous for the mutation, which was not found in 100 controls.


REFERENCES

  1. Akhmedov, N. B., Piriev, N. I., Chang, B., Rapoport, A. L., Hawes, N. L., Nishina, P. M., Nusinowitz, S., Heckenlively, J. R., Roderick, T. H., Kozak, C. A., Danciger, M., Davisson, M. T., Farber, D. B. A deletion in a photoreceptor-specific nuclear receptor mRNA causes retinal degeneration in the rd7 mouse. Proc. Nat. Acad. Sci. 97: 5551-5556, 2000. [PubMed: 10805811, images, related citations] [Full Text]

  2. Bernal, S., Solans, T., Gamundi, M. J., Hernan, I., de Jorge, L., Carballo, M., Navarro, R., Tizzano, E., Ayuso, C., Baiget, M. Analysis of the involvement of the NR2E3 gene in autosomal recessive retinal dystrophies. Clin. Genet. 73: 360-366, 2008. [PubMed: 18294254, related citations] [Full Text]

  3. Bowes, C., Danciger, M., Kozak, C. A., Farber, D. B. Isolation of a candidate cDNA for the gene causing retinal degeneration in the rd mouse. Proc. Nat. Acad. Sci. 86: 9722-9726, 1989. Note: Erratum: Proc. Nat. Acad. Sci. 87: 1625 only, 1990. [PubMed: 2481314, related citations] [Full Text]

  4. Cheng, H., Khanna, H., Oh, E. C. T., Hicks, D., Mitton, K. P., Swaroop, A. Photoreceptor-specific nuclear receptor NR2E3 functions as a transcriptional activator in rod photoreceptors. Hum. Molec. Genet. 13: 1563-1575, 2004. [PubMed: 15190009, related citations] [Full Text]

  5. Coppieters, F., Leroy, B. P., Beysen, D., Hellemans, J., De Bosscher, K., Haegeman, G., Robberecht, K., Wuyts, W., Coucke, P. J., De Baere, E. Recurrent mutation in the first zinc finger of the orphan nuclear receptor NR2E3 causes autosomal dominant retinitis pigmentosa. Am. J. Hum. Genet. 81: 147-157, 2007. [PubMed: 17564971, images, related citations] [Full Text]

  6. Gerber, S., Rozet, J.-M., Takezawa, S.-I., Coutinho dos Santos, L., Lopes, L., Gribouval, O., Penet, C., Perrault, I., Ducroq, D., Souied, E., Jeanpierre, M., Romana, S., Frezal, J., Ferraz, F., Yu-Umesono, R., Munnich, A., Kaplan, J. The photoreceptor cell-specific nuclear receptor gene (PNR) accounts for retinitis pigmentosa in the Crypto-Jews from Portugal (Marranos), survivors from the Spanish Inquisition. Hum. Genet. 107: 276-284, 2000. [PubMed: 11071390, related citations] [Full Text]

  7. Haider, N. B., Jacobson, S. G., Cideciyan, A. V., Swiderski, R., Streb, L. M., Searby, C., Beck, G., Hockey, R., Hanna, D. B., Gorman, S., Duhl, D., Carmi, R., Bennett, J., Weleber, R. G., Fishman, G. A., Wright, A. F., Stone, E. M., Sheffield, V. C. Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nature Genet. 24: 127-131, 2000. [PubMed: 10655056, related citations] [Full Text]

  8. Haider, N. B., Naggert, J. K., Nishina, P. M. Excess cone cell proliferation due to lack of a functional NR2E3 causes retinal dysplasia and degeneration in rd7/rd7 mice. Hum. Molec. Genet. 10: 1619-1626, 2001. [PubMed: 11487564, related citations] [Full Text]

  9. Kannabiran, C., Singh, H., Sahini, N., Jalali, S., Mohan, G. Mutations in TULP1, NR2E3, and MFRP genes in Indian families with autosomal recessive retinitis pigmentosa. Molec. Vision 18: 1165-1174, 2012. [PubMed: 22605927, images, related citations]

  10. Kobayashi, M., Takezawa, S., Hara, K., Yu, R. T., Umesono, Y., Agata, K., Taniwaki, M., Yasuda, K., Umesono, K. Identification of a photoreceptor cell-specific nuclear receptor. Proc. Nat. Acad. Sci. 96: 4814-4819, 1999. [PubMed: 10220376, images, related citations] [Full Text]

  11. Milam, A. H., Rose, L., Cideciyan, A. V., Barakat, M. R., Tang, W.-X., Gupta, N., Aleman, T. S., Wright, A. F., Stone, E. M., Sheffield, V. C., Jacobson, S. G. The nuclear receptor NR2E3 plays a role in human retinal photoreceptor differentiation and degeneration. Proc. Nat. Acad. Sci. 99: 473-478, 2002. [PubMed: 11773633, images, related citations] [Full Text]

  12. Peng, G.-H., Ahmad, O., Ahmad, F., Liu, J., Chen, S. The photoreceptor-specific nuclear receptor Nr2e3 interacts with Crx and exerts opposing effects on the transcription of rod versus cone genes. Hum. Molec. Genet. 14: 747-764, 2005. [PubMed: 15689355, related citations] [Full Text]

  13. Rendtorff, N. D., Vissing, H., Tumer, Z., Silahtaroglu, A., Tommerup, N. Assignment of the NR2E3 gene to mouse chromosome 9 and to human chromosome 15q22.33-q23. Cytogenet. Cell Genet. 89: 279-280, 2000. [PubMed: 10965145, related citations] [Full Text]


Marla J. F. O'Neill - updated : 2/19/2015
Marla J. F. O'Neill - updated : 11/24/2008
George E. Tiller - updated : 4/25/2008
Victor A. McKusick - updated : 6/19/2007
George E. Tiller - updated : 1/16/2007
George E. Tiller - updated : 1/16/2007
Victor A. McKusick - updated : 1/31/2002
George E. Tiller - updated : 12/19/2001
Carol A. Bocchini - updated : 1/16/2001
Victor A. McKusick - updated : 10/3/2000
Victor A. McKusick - updated : 7/21/2000
Creation Date:
Victor A. McKusick : 1/31/2000
alopez : 02/21/2017
carol : 05/18/2016
alopez : 2/25/2015
mcolton : 2/19/2015
terry : 8/31/2012
alopez : 3/30/2011
wwang : 12/1/2008
terry : 11/24/2008
wwang : 4/28/2008
terry : 4/25/2008
carol : 7/10/2007
alopez : 6/21/2007
alopez : 6/21/2007
terry : 6/19/2007
alopez : 1/17/2007
terry : 1/16/2007
terry : 1/16/2007
carol : 8/19/2004
carol : 2/18/2002
mcapotos : 2/7/2002
terry : 1/31/2002
cwells : 1/3/2002
cwells : 12/19/2001
carol : 1/16/2001
terry : 11/8/2000
carol : 10/20/2000
mcapotos : 10/12/2000
mcapotos : 10/9/2000
terry : 10/3/2000
alopez : 7/26/2000
terry : 7/21/2000
alopez : 1/31/2000

* 604485

NUCLEAR RECEPTOR SUBFAMILY 2, GROUP E, MEMBER 3; NR2E3


Alternative titles; symbols

PHOTORECEPTOR-SPECIFIC NUCLEAR RECEPTOR; PNR


HGNC Approved Gene Symbol: NR2E3

SNOMEDCT: 232065000;  


Cytogenetic location: 15q23     Genomic coordinates (GRCh38): 15:71,810,554-71,818,253 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
15q23 Enhanced S-cone syndrome 268100 Autosomal recessive 3
Retinitis pigmentosa 37 611131 Autosomal dominant; Autosomal recessive 3

TEXT

Description

PNR, also known as NR2E3, encodes a retinal nuclear receptor that is a ligand-dependent transcription factor. The NR2E3 protein is part of a large family of nuclear receptor transcription factors involved in signaling pathways. Nuclear receptors have been shown to regulate pathways involved in embryonic development, as well as maintenance of proper cell function in adults. Members of this family are characterized by discrete domains that function in DNA and ligand binding.


Cloning and Expression

Kobayashi et al. (1999) identified a photoreceptor cell-specific nuclear receptor, designated PNR for 'photoreceptor-specific nuclear receptor,' that contains a unique proximal (P) box (CNGCSG) in the DNA-binding domain. By searching an EST database for vertebrate homologs of Drosophila 'tailless' (tll), Kobayashi et al. (1999) found a highly related partial human sequence that had been identified in an adult retina cDNA library. They obtained a full-length cDNA from a retinoblastoma cell line using RT-PCR and 3-prime RACE. Analysis of the 410-amino acid PNR sequence revealed a characteristic nuclear receptor structure, with a DNA-binding domain followed by a putative ligand-binding domain. The overall structure of PNR was most closely related to that of TLX (603849). In human cell lines, PNR expression was observed in retinoblastoma along with other photoreceptor marker genes such as CRX (602225). PNR was able to recognize a subset of TLX target sequences in vitro.

By Northern blot analysis, Haider et al. (2000) detected expression of a major 2.2-kb mature NR2E3 mRNA in normal human eye restricted to the neurosensory retina. By in situ hybridization, Haider et al. (2000) detected NR2E3 transcripts solely in the outer nuclear layer of the adult human neurosensory retina, where the nuclei of cone and rod photoreceptors reside.


Gene Structure

Kobayashi et al. (1999) determined that the PNR coding region contains 8 exons and spans 7 kb.


Gene Function

Cheng et al. (2004) reported that Nr2e3 expression was localized preferentially to the rod, and not to the cone, photoreceptor nuclei in rodent retina. Interaction with another orphan nuclear receptor, Nr1d1 (Rev-erb-alpha; 602408), was observed using multiple methods. In transient transfection studies, both Nr2e3 and Nr1d1 activated the promoters of rod phototransduction genes synergistically with neural retina leucine zipper (NRL; 162080) and cone-rod homeobox (CRX; 602225). All 4 proteins, Nr2e3, Nr1d1, Nrl, and Crx, could be coimmunoprecipitated from bovine retinal nuclear extracts, suggesting a multiprotein transcriptional regulatory complex. The authors suggested that NR2E3 may be involved in regulating the expression of rod photoreceptor-specific genes and may play a role in transcriptional regulatory network(s) during rod differentiation.

Using yeast 2-hybrid screens with Nr2e3 as bait, Peng et al. (2005) identified Crx as an interacting partner of Nr2e3. Immunoprecipitation assays confirmed the interaction and identified the DNA-binding domain of each protein as the interaction motif. Immunohistochemistry demonstrated that Crx and Nr2e3 were coexpressed by rod photoreceptors and their precursors. Chromatin immunoprecipitation assays on mouse retina demonstrated that Nr2e3 and Crx cooccupied the promoter/enhancer region of several rod and cone genes in the rod photoreceptor cells. The promoter/enhancer occupancy of Nr2e3 was Crx-dependent, suggesting that Nr2e3 may be associated with photoreceptor gene targets by interacting with Crx. Transient transfection assays demonstrated that Nr2e3 enhanced rhodopsin (180380), but repressed S- or M-cone opsin transcription when interacting with Crx. Quantitative real-time RT-PCR analysis on postnatal day 28 retina of the rd7 mouse revealed an upregulation of cone genes, but downregulation of rod genes. Several mutant forms of human NR2E3 identified from enhanced S-cone syndrome (ESCS; 268100) patients showed defects in interacting with Crx and/or in transcriptional regulatory function. Peng et al. (2005) suggested that NR2E3 may be a dual-function transcriptional regulator that acts in concert with CRX to promote and maintain the function of rod photoreceptors.


Mapping

Kobayashi et al. (1999) mapped the NR2E3 gene to 15q24 by fluorescence in situ hybridization. By radiation hybrid analysis and FISH, Rendtorff et al. (2000) mapped the NR2E3 gene to 15q22.3-q23. Haider et al. (2000) mapped the NR2E3 gene as part of their search for the chromosome 15-linked Bardet-Biedl syndrome gene. The NR2E3 genomic sequence was contained within a single BAC that resided between markers D15S131 and D15S204 on chromosome 15q23.


Molecular Genetics

Enhanced S-Cone Syndrome

Haider et al. (2000) analyzed NR2E3 sequence in families with Bardet-Biedl syndrome linked to chromosome 15 (BBS4; see 209900), as well as affected individuals from 50 additional BBS families with unknown linkage. They found no disease-causing mutations. They then screened a cohort of 400 patients with retinal degenerative disease, including a small subset of patients with enhanced S-cone syndrome (ESCS; 268100). They found plausible disease-causing NR2E3 mutations only in ESCS patients. A wider study of 35 individuals with ESCS, representing 3 consanguineous kindreds and 26 simplex families, including a set of monozygotic twins, revealed 12 different mutations in the NR2E3 gene. A mutation was found in NR2E3 in 94% of the patients.

The enhanced S-cone syndrome is the only inherited retinal disorder that shows increased visual function involving the minority S (blue) cones, and decreased rod and L/M (red/green) cone function. The disorder may result from abnormal cell-fate determination, leading to excess S cones at the expense of other photoreceptor subtypes. In 16 ESCS patients with the most common NR2E3 mutation, R311Q (604485.0005), Milam et al. (2002) documented an abnormal ratio of S- to L/M-cone function and progressive retinal degeneration. They studied the postmortem retina of an ESCS patient homozygous for the NR2E3 R311Q mutation. No rods were identified, but cones were increased approximately 2-fold, and 92% were S cones. Only 15% of the cones expressed L/M-cone opsin and some coexpressed S-cone opsin. The retina was disorganized, with densely packed cones intermixed with inner retinal neurons. The retina was also degenerate, retaining photoreceptors in only the central and far peripheral regions. These observations suggested a role for NR2E3 in regulation of human photoreceptor development. Degeneration of the NR2E3 retina may result from defective development, known S-cone fragility, or abnormal maintenance of mature photoreceptors.

Gerber et al. (2000) studied members of a highly consanguineous endogamous population of Crypto-Jews living in a mountainous area of Portugal with what may have been enhanced S-cone syndrome. Crypto-Jews are survivors of Spanish Jews who were persecuted in the late 15th century, escaped to Portugal, and were forced to convert to save their lives. By a genomewide search for homozygosity, Gerber et al. (2000) mapped the disease locus to 15q22-q24 in the region where the PNR gene is located. They identified homozygosity for the R311Q mutation in the NR2E3 gene, as the cause of the disorder in this population. Because of the closed nature of the population, Gerber et al. (2000) were not able to perform S-cone testing to confirm the diagnosis.

Goldmann-Favre Syndrome

In a 13-year-old boy with Goldmann-Favre syndrome (GFS; see 268100), a severe form of ESCS, Bernal et al. (2008) identified homozygosity for the R311Q mutation in the NR2E3 gene.

Retinitis Pigmentosa 37

Coppieters et al. (2007) identified a heterozygous missense mutation (G56R; 604485.0006) in the first zinc finger of the NR2E3 gene in a large Belgian family with autosomal dominant retinitis pigmentosa. Overall, this missense mutation was found in 3 families affected with adRP among 87 unrelated families with potentially dominant retinal dystrophies (3.4%), of which 47 were affected with RP (6.4%). Affected members of these families displayed a novel recognizable clinical subtype of adRP (611131). Other mutations of NR2E3 had been shown to cause autosomal recessive RP and enhanced S-cone syndrome (268100). Coppieters et al. (2007) proposed a different pathogenetic mechanism for these distinct dominant and recessive phenotypes, which may be attributable to the dual key role of NR2E3 in the regulation of photoreceptor-specific genes during rod development and maintenance.

Bernal et al. (2008) analyzed the NR2E3 gene in 96 patients with autosomal recessive retinitis pigmentosa, 3 patients with Goldmann-Favre syndrome (GFS), and 4 patients with retinoschisis who were negative for mutation in the XLRS1 gene (300839), and identified homozygosity for 3 different mutations in 1 patient with GFS and 5 with arRP (604485.0001, 604485.0005, and 604485.0007, respectively).

In a brother and sister with RP from a consanguineous southern Indian family, Kannabiran et al. (2012) identified homozygosity for a complex frameshift mutation in the NR2E3 gene (604485.0008).


Animal Model

The autosomal recessive retinal degeneration of the rd7 mouse was identified at the Jackson Laboratory. It causes retinal folding associated with retinal spots and late-onset retinal degeneration. Akhmedov et al. (2000) mapped the mutation to mouse chromosome 9 in a region homologous to human 15q23-q25. In studies of a pool of cDNAs generated by subtractive hybridization of mRNAs from normal and photoreceptorless rd mouse retinas (Bowes et al., 1989), Akhmedov et al. (2000) identified several photoreceptor-specific clones and mapped them to their chromosomal loci. One of these cDNAs, which corresponded to the PNR gene, mapped near the rd7 locus, making PNR a candidate gene. They identified a 380-nucleotide deletion in the coding region of the rd7 PNR message that created a frameshift and produced a premature stop codon. This deletion accounted for more than 32% of the normal protein and eliminated a portion of the DNA-binding domain. In addition, it may result in the rapid degradation of the rd7 PNR message by the nonsense-mediated decay pathway, preventing the synthesis of the corresponding protein. Their findings demonstrated that PNR expression is critical for the normal development and function of the photoreceptor cells.

Haider et al. (2001) determined that the rd7 phenotype results from a splicing error created by a genomic deletion of intron 4 and part of exon 4 in the Nr2e3 gene. Rd7 retinal tissue displayed whorls in the outer nuclear layer which were not apparent until postnatal day 12.5. The Nr2e3 message was abundant by postnatal day 2.5, prior to the development of S-cones. The data coincided with studies in humans showing that mutations in the Nr2e3 gene result in a unique type of retinal degeneration known as enhanced S-cone syndrome, where patients have a 30-fold increase in S-cone sensitivity compared to normal. Immunohistochemical staining of cone cells demonstrated that rd7 retinas have an increased number of cone cells compared to wildtype retinas. The authors proposed that Nr2e3 may function by regulating genes involved in cone cell proliferation, and mutations in this gene may lead to retinal dysplasia and degeneration by disrupting normal photoreceptor cell topography as well as cell-cell interactions.


ALLELIC VARIANTS 8 Selected Examples):

.0001   ENHANCED S-CONE SYNDROME

RETINITIS PIGMENTOSA 37, INCLUDED
NR2E3, IVS1AS, A-C
SNP: rs2723341, gnomAD: rs2723341, ClinVar: RCV000005864, RCV000171236, RCV000185571, RCV000261643, RCV000505031, RCV000507553, RCV000626919, RCV000668212, RCV000678584, RCV000787627, RCV001275369, RCV002243841, RCV002515235

Enhanced S-Cone Syndrome

In 3 affected individuals of an extensive kindred with enhanced S-cone syndrome (ESCS; 268100), Haider et al. (2000) identified homozygosity for a splice acceptor site mutation, an A-to-C transversion in the splice acceptor site of intron 1 of the NR2E3 gene. Another distantly related affected family member was found to be heterozygous for the mutation, which was also identified in 8 simplex probands with ESCS. The mutation was not found in 500 control individuals.

Retinitis Pigmentosa 37

In a brother and sister with retinitis pigmentosa and hypopigmented clumped lesions in the posterior pole of both eyes (RP37; 611131), Bernal et al. (2008) identified homozygosity for the 119-2A-C splice acceptor mutation in intron 1 of the NR2E3 gene. Analysis of the RT-PCR products from the mRNA transcripts generated in transient expression studies showed that the mutation generated an aberrant splicing mechanism. The mutation was not found in 60 blood donor controls.


.0002   ENHANCED S-CONE SYNDROME

NR2E3, ARG76TRP
SNP: rs104894492, gnomAD: rs104894492, ClinVar: RCV000005866, RCV001048873, RCV003323352, RCV003887854

In 2 patients with enhanced S-cone syndrome (ESCS; 268100), Haider et al. (2000) identified a C-to-T transition in the NR2E3 gene, resulting in an arg76-to-trp substitution.


.0003   ENHANCED S-CONE SYNDROME

NR2E3, ARG76GLN
SNP: rs104894493, gnomAD: rs104894493, ClinVar: RCV000005867, RCV000261496, RCV000668029, RCV001045323, RCV001075864, RCV001449793

In a patient with enhanced S-cone syndrome (ESCS; 268100), Haider et al. (2000) identified an arg76-to-gln mutation resulting from a G-to-A transition in the NR2E3 gene.


.0004   ENHANCED S-CONE SYNDROME

NR2E3, 9-BP DEL
SNP: rs1567159701, ClinVar: RCV000005868

In a patient with enhanced S-cone syndrome (ESCS; 268100), Haider et al. (2000) identified deletion of 9 bp of the NR2E3 gene, resulting in a 3-amino acid deletion (codons 67-69) in the NR2E3 protein.


.0005   ENHANCED S-CONE SYNDROME

GOLDMANN-FAVRE SYNDROME, INCLUDED
NR2E3, ARG311GLN
SNP: rs28937873, gnomAD: rs28937873, ClinVar: RCV000005869, RCV000005870, RCV000171240, RCV000393548, RCV000668086, RCV000787633, RCV001074891, RCV001095701, RCV001257807, RCV001374877

Enhanced S-Cone Syndrome

In Crypto-Jews (Marranos) in Portugal with what may have been enhanced S-cone syndrome (ESCS; 268100), Gerber et al. (2000) identified a 1020G-A transition in exon 6 of the NR2E3 gene, resulting in an arg311-to-gln (R311Q) substitution. Clinical evidence of retinitis pigmentosa started in the first decade with night blindness, followed during the second and third decades by a slow concentric reduction of the visual field. Visual acuity decreased around 40 years of age, but affected individuals were not completely blind even when elderly. The fundus showed typical features of RP, i.e., pigment deposits in the peripheral retina, retinal pigment epithelium atrophy, and waxy pallor of the optic nerve. Because of the closed nature of the population, Gerber et al. (2000) were not able to perform S-cone testing. They noted, however, that Haider et al. (2000) had identified the R311Q mutation in 13 of 29 unrelated patients (44.8%) who were thought to have enhanced S-cone syndrome.

Goldmann-Favre Syndrome

In a 13-year-old boy with Goldmann-Favre syndrome (GFS; see 268100), Bernal et al. (2008) identified homozygosity for the R311Q mutation in the NR2E3 gene. The mutation was not found in 60 blood donor controls.


.0006   RETINITIS PIGMENTOSA 37

NR2E3, GLY56ARG
SNP: rs121912631, ClinVar: RCV000005871, RCV000286602, RCV000787628, RCV001075751

In 3 families, 2 Belgian, 1 French, Coppieters et al. (2007) found that autosomal dominant retinitis pigmentosa (RP37; 611131) resulted from a 166G-A transition in exon 2 of the NR2E3 gene that caused a gly56-to-arg (G56R) amino acid substitution.


.0007   RETINITIS PIGMENTOSA 37

NR2E3, 5-BP DEL, NT1034
SNP: rs1567160967, ClinVar: RCV000005872

In 2 sisters and their brother with retinitis pigmentosa (RP37; 611131), born of consanguineous parents, Bernal et al. (2008) identified homozygosity for a 5-bp deletion in exon 7 of the NR2E3 gene, predicted to generate a stop signal in codon 345 and result in a protein lacking part of the ligand-binding domain. Dilated funduscopic examination revealed minimal or no retinal vessel attenuation and the presence of clusters of large, clumped pigment deposits with vitreous floaters in the midperiphery of both eyes. The mutation was not found in 60 blood donor controls.


.0008   RETINITIS PIGMENTOSA 37

NR2E3, 2-BP DEL/25-BP INS, NT143
SNP: rs730882149, ClinVar: RCV000162027, RCV001449814

In a brother and sister from a consanguineous southern Indian family with retinitis pigmentosa mapping to chromosome 15 (RP37; 611131), Kannabiran et al. (2012) identified homozygosity for a 2-bp deletion and 25-bp insertion at codon 48 in exon 2 of the NR2E3 gene (c.143_144delGCins25), causing a frameshift predicted to result in a premature termination codon after 65 amino acids. The unaffected parents were heterozygous for the mutation, which was not found in 100 controls.


REFERENCES

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  8. Haider, N. B., Naggert, J. K., Nishina, P. M. Excess cone cell proliferation due to lack of a functional NR2E3 causes retinal dysplasia and degeneration in rd7/rd7 mice. Hum. Molec. Genet. 10: 1619-1626, 2001. [PubMed: 11487564] [Full Text: https://doi.org/10.1093/hmg/10.16.1619]

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  10. Kobayashi, M., Takezawa, S., Hara, K., Yu, R. T., Umesono, Y., Agata, K., Taniwaki, M., Yasuda, K., Umesono, K. Identification of a photoreceptor cell-specific nuclear receptor. Proc. Nat. Acad. Sci. 96: 4814-4819, 1999. [PubMed: 10220376] [Full Text: https://doi.org/10.1073/pnas.96.9.4814]

  11. Milam, A. H., Rose, L., Cideciyan, A. V., Barakat, M. R., Tang, W.-X., Gupta, N., Aleman, T. S., Wright, A. F., Stone, E. M., Sheffield, V. C., Jacobson, S. G. The nuclear receptor NR2E3 plays a role in human retinal photoreceptor differentiation and degeneration. Proc. Nat. Acad. Sci. 99: 473-478, 2002. [PubMed: 11773633] [Full Text: https://doi.org/10.1073/pnas.022533099]

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Contributors:
Marla J. F. O'Neill - updated : 2/19/2015
Marla J. F. O'Neill - updated : 11/24/2008
George E. Tiller - updated : 4/25/2008
Victor A. McKusick - updated : 6/19/2007
George E. Tiller - updated : 1/16/2007
George E. Tiller - updated : 1/16/2007
Victor A. McKusick - updated : 1/31/2002
George E. Tiller - updated : 12/19/2001
Carol A. Bocchini - updated : 1/16/2001
Victor A. McKusick - updated : 10/3/2000
Victor A. McKusick - updated : 7/21/2000

Creation Date:
Victor A. McKusick : 1/31/2000

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