Other entities represented in this entry:
ORPHA: 53540; DO: 0090059;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q23 | Enhanced S-cone syndrome | 268100 | Autosomal recessive | 3 | NR2E3 | 604485 |
A number sign (#) is used with this entry because enhanced S-cone syndrome (ESCS) is caused by homozygous or compound heterozygous mutation in the nuclear receptor gene NR2E3 (604485) on chromosome 15q23.
Hereditary human retinal degenerative diseases usually affect the mature photoreceptor topography by reducing the number of cells through apoptosis, resulting in loss of visual function. Only one inherited retinal disease, the enhanced S-cone syndrome (ESCS), manifests a gain in function of photoreceptors. ESCS is an autosomal recessive retinopathy in which patients have increased sensitivity to blue light; perception of blue light is mediated by what is normally the least populous cone photoreceptor subtype, the S (short wavelength, blue) cones. People with ESCS also suffer visual loss, with night blindness occurring from early in life, varying degrees of L (long, red)- and M (middle, green)-cone vision, and retinal degeneration. The pattern of retinal dysfunction is a constant among ESCS patients, but the degree of clinically evident retinal degeneration can vary from minimal to severe. The latter condition is known as Goldmann-Favre syndrome. Haider et al. (2000) suggested that the altered ratio of S- to L/M-cone photoreceptor sensitivity in ESCS may be due to abnormal cone cell fate determination during retinal development.
Goldmann-Favre syndrome is characterized by a liquefied vitreous body with preretinal band-shaped structures (veil), macular changes in the form of retinoschisis or edema and pigmentary degeneration of the retina with hemeralopia and extinguished electroretinogram. Cataract is a complication. The disorder is to be distinguished from X-linked retinoschisis (312700) and from autosomal dominant hyaloideoretinal degeneration (143200). Favre (1958) described a brother and sister, aged 16 and 15 years, respectively, with hemeralopia, degenerative vitreous changes, peripheral and central retinoschisis, etc. Ricci (1960) added a case. MacVicar and Wilbrandt (1970) described the disorder in 2 brothers whose parents were related. Night blindness had been present since childhood.
Jacobson et al. (1990, 1991) described the enhanced S-cone syndrome. Hood et al. (1995) speculated that the disorder is caused by a defect in the determination of photoreceptor identity. Rods, cones, and all other types of retinal cells are generated by multipotent progenitor cells. Cones are generated relatively early during retinal development, whereas rods are born during a comparatively late phase (Cepko, 2000) as far as the development of the retina is concerned.
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. 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.
Jacobson et al. (2004) showed that early human NR2E3 disease with S-cone hyperfunction displayed thickened retinal layers within an otherwise normally structured retina. With visual loss, however, lamination was coarse and there was a strikingly thick and bulging appearance to the retina, localized to an annulus encircling the central fovea. This pattern was not found in other retinal degenerations. The authors hypothesized that the abnormal laminar retinal architecture of early NR2E3 disease may be due in part to larger cells with an S-cone phenotype in place of rods that failed to differentiate. The later-stage dysplastic appearance suggested a previously unrecognized proliferative response in human retinal degeneration.
Bernal et al. (2008) examined a 13-year-old boy with night blindness and a gradual decrease in visual acuity of the right eye who had been diagnosed with Goldmann-Favre syndrome. Dilated funduscopic examination revealed peripheral retinoschisis and macular cysts in both eyes, and intraretinal pigmentation with a nummular pattern. Optical coherence tomography showed macular schisis; electroretinograms were not recordable in either eye.
Cideciyan et al. (2003) studied the relationship between cone deactivation kinetics in patients with the enhanced S-cone syndrome caused by mutations in NR2E3 and the immunoreactivity to GRK1 (180381) and GRK7 (606987). Normal deactivation kinetics in human L/M cones could occur without GRK7 when GRK1 was present in ESCS, but did not occur when GRK7 was present but GRK1 was deficient in Oguchi disease (258100). Lack of both GRK1 and GRK7 in S cones of patients with ESCS resulted in a more pronounced abnormality in deactivation kinetics and suggested the existence of partial compensation by either GRK when the other was deficient.
In a group of ESCS probands, Haider et al. (2000) found mutations in the NR2E3 gene (see, e.g., 604485.0001-604485.0004), also known as PNR, which encodes a retinal nuclear receptor found by Kobayashi et al. (1999) to be a ligand-dependent transcription factor.
Gerber et al. (2000) identified an R311Q mutation in the NR2E3 gene (604485.0005) in a group of Crypto-Jews (Marranos) in Portugal with what may have been ESCS: because of the closed nature of the population, Gerber et al. (2000) were not able to perform S-cone testing, but they noted that Haider et al. (2000) had identified the R311Q mutation in 13 of 29 unrelated patients (44.8%) who were thought to have ESCS.
In a 13-year-old boy diagnosed with Goldmann-Favre syndrome, Bernal et al. (2008) identified homozygosity for the R311Q mutation in the NR2E3 gene.
The rd7 mutant mouse has a retinopathy caused by mutation in the same gene as that which is mutant in Goldmann-Favre syndrome; thus, it is a good model of a human disease (Akhmedov et al., 2000).
See 310500 for a discussion of the use of the term hemeralopia to mean night blindness, particularly in the francophone medical literature.
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] [Full Text: https://doi.org/10.1073/pnas.97.10.5551]
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] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.00963.x]
Cepko, C. Giving in to the blues. Nature Genet. 24: 99-100, 2000. [PubMed: 10655045] [Full Text: https://doi.org/10.1038/72887]
Cideciyan, A. V., Jacobson, S. G., Gupta, N., Osawa, H., Locke, K. G., Weiss, E. R., Wright, A. F., Birch, D. G., Milam, A. H. Cone deactivation kinetics and GRK1/GRK7 expression in enhanced S cone syndrome caused by mutations in NR2E3. Invest. Ophthal. Vis. Sci. 44: 1268-1274, 2003. [PubMed: 12601058] [Full Text: https://doi.org/10.1167/iovs.02-0494]
Favre, M. A propos de deux cas de degenerescence hyaloideoretinienne. Two cases of hyaloid-retinal degeneration. Ophthalmologica 135: 604-609, 1958. [PubMed: 13553271] [Full Text: https://doi.org/10.1159/000303360]
Francois, J., De Rouck, A., Cambie, E. Degenerescence hyaloideo-tapeto-retinienne de Goldmann-Favre. Ophthalmologica 168: 81-96, 1974. [PubMed: 4546336] [Full Text: https://doi.org/10.1159/000307026]
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] [Full Text: https://doi.org/10.1007/s004390000350]
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] [Full Text: https://doi.org/10.1038/72777]
Hood, D. C., Cideciyan, A. V., Roman, A. J., Jacobson, S. G. Enhanced S cone syndrome: evidence for an abnormally large number of S cones. Vision Res. 35: 1473-1481, 1995. [PubMed: 7645276] [Full Text: https://doi.org/10.1016/0042-6989(95)98727-q]
Jacobson, S. G., Marmor, M. F., Kemp, C. M., Knighton, R. W. SWS (blue) cone hypersensitivity in a newly identified retinal degeneration. Invest. Ophthal. Vis. Sci. 31: 827-838, 1990. [PubMed: 2335450]
Jacobson, S. G., Roman, A. J., Roman, M. I., Gass, J. D. M., Parker, J. A. Relatively enhanced S cone function in the Goldmann-Favre syndrome. Am. J. Ophthal. 111: 446-453, 1991. [PubMed: 2012146] [Full Text: https://doi.org/10.1016/s0002-9394(14)72379-7]
Jacobson, S. G., Sumaroka, A., Aleman, T. S., Cideciyan, A. V., Schwartz, S. B., Roman, A. J., McInnes, R. R., Sheffield, V. C., Stone, E. M., Swaroop, A., Wright, A. F. Nuclear receptor NR2E3 gene mutations distort human retinal laminar architecture and cause an unusual degeneration. Hum. Molec. Genet. 13: 1893-1902, 2004. [PubMed: 15229190] [Full Text: https://doi.org/10.1093/hmg/ddh198]
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]
MacVicar, J. E., Wilbrandt, H. R. Hereditary retinoschisis and early hemeralopia: a report of two cases. Arch. Ophthal. 83: 629-636, 1970. [PubMed: 5309737] [Full Text: https://doi.org/10.1001/archopht.1970.00990030629020]
Ricci, A. Clinique et transmission genetique des differentes formes de degenerescences vitreo-retiniennes. Ophthalmologica 139: 338-342, 1960.