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Japanese Journal of Ophthalmology

, Volume 60, Issue 6, pp 476–485 | Cite as

New truncation mutation of the NR2E3 gene in a Japanese patient with enhanced S-cone syndrome

  • Kazuki KuniyoshiEmail author
  • Takaaki Hayashi
  • Hiroyuki Sakuramoto
  • Hiroshi Mishima
  • Hiroshi Tsuneoka
  • Kazushige Tsunoda
  • Takeshi Iwata
  • Yoshikazu Shimomura
Clinical Investigation

Abstract

Purpose

The enhanced S-cone syndrome (ESCS) is a rare hereditary retinal degeneration that has enhanced short wavelength-sensitive cone (S-cone) functions. The longitudinal clinical course of this disease has been rarely reported, and the genetic aspects of ESCS have not been well investigated in the Japanese population. In this report, we present our clinical and genetic findings for 2 patients with ESCS.

Patients and methods

The patients were 2 unrelated Japanese men. Standard ophthalmic examinations and mutation screening for the NR2E3 gene were performed.

Results

Patient 1 was a 36-year-old man, and his clinical findings were typical of ESCS. His decimal best-corrected visual acuity (BCVA) was 1.0 OD and 0.5 OS after removal of cataracts. Genetic investigations revealed a homozygous truncation frameshift, the p.I307LfsX33 mutation. Patient 2 was an 11-year-old boy when he was first examined by us. His clinical findings were typical of ESCS except for uveitis in the left eye. His decimal BCVA at the age of 39 years was maintained at 1.5 in each eye, although the retinal degeneration and visual field impairments had progressed during the follow-up period. The genetic investigations revealed homozygous mutations of p.R104Q in the NR2E3 gene.

Conclusions

The frameshift mutation, p.I307LfsX33, in the NR2E3 gene is a new causative mutation for ESCS. The clinical observations for patient 2 are the longest ever reported. The retinal degeneration caused by this mutation is slowly progressive, and these patients maintained good vision with maintenance of the foveal structure until their late thirties.

Keywords

Enhanced S-cone syndrome Electroretinogram Goldmann-Favre syndrome NR2E3 Optical coherence tomography 

Notes

Acknowledgments

We thank the patients and their families for their kind participation in this study; Professor Kunihiko Shiraki and Doctor Kumiko Hirayama of Department of Ophthalmology and Visual Science, Graduate School of Medicine, Osaka City University, for providing precise clinical data on the parents of patient 1; Professor Emeritus Duco I. Hamasaki of the Bascom Palmer Eye Institute of the University of Miami, for his critical discussion and final manuscript editing. This research was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan [Grant-in-Aid for Scientific Research (C) 2546738] and the Japan Agency for Medical Research and Development (Practical Research Project for Rare/Intractable Diseases, 15ek0109072h0002 and 26310601).

Conflicts of interest

K. Kuniyoshi, None; T. Hayashi, None; H. Sakuramoto, None; H. Mishima, None; H. Tsuneoka, None; K. Tsunoda, None; T. Iwata, None; Y. Shimomura, None.

References

  1. 1.
    Online Mendelian inheritance in man (OMIM). In: National Center for Biotechnology Information (NCBI), U.S. National Library of Medicine. 2016. http://www.ncbi.nlm.nih.gov/omim. Accessed 29 Apr 2016.
  2. 2.
    Marmor MF, Jacobson SG, Foerster MH, Kellner U, Weleber RG. Diagnostic clinical findings of a new syndrome with night blindness, maculopathy, and enhanced S cone sensitivity. Am J Ophthalmol. 1990;110:124–34.CrossRefPubMedGoogle Scholar
  3. 3.
    Jacobson SG, Marmor MF, Kemp CM, Knighton RW. SWS (blue) cone hypersensitivity in a newly identified retinal degeneration. Invest Ophthalmol Vis Sci. 1990;31:827–38.PubMedGoogle Scholar
  4. 4.
    Kellner U, Zrenner E, Sadowski B, Foerster MH. Enhanced S cone sensitivity syndrome: long-term follow-up, electrophysiological and psychophysical findings. Clin Vis Sci. 1993;8:425–34.Google Scholar
  5. 5.
    Pachydaki SI, Bhatnagar PA, Barbazetto IA, Klaver CC, Freund BK, Yannuzzi LA. Long-term follow-up in enhanced S-cone syndrome. Retin Cases Brief Rep. 2009;3:118–20.CrossRefPubMedGoogle Scholar
  6. 6.
    Kuniyoshi K, Hayashi T, Sakuramoto H, Nakao A, Sato T, Utsumi T, et al. Novel mutations in enhanced S-cone syndrome. Ophthalmology. 2013;120:431–431e.6.CrossRefPubMedGoogle Scholar
  7. 7.
    Nakamura Y, Hayashi T, Kozaki K, Kubo A, Omoto S, Watanabe A, et al. Enhanced S-cone syndrome in a Japanese family with a nonsense NR2E3 mutation (Q350X). Acta Ophthalmol Scand. 2004;82:616–22.CrossRefPubMedGoogle Scholar
  8. 8.
    Usui T, Ichibe M, Tanimoto N, Ueki S, Takagi M, Hasegawa S, et al. Ocular fundus images by scanning laser ophthalmoscopy in a patient with enhanced S-cone syndrome. Retina. 2004;24:946–52.CrossRefPubMedGoogle Scholar
  9. 9.
    Hayashi T, Gekka T, Goto-Omoto S, Takeuchi T, Kubo A, Kitahara K. Novel NR2E3 mutations (R104Q, R334G) associated with a mild form of enhanced S-cone syndrome demonstrate compound heterozygosity. Ophthalmology. 2005;112:2115–22.PubMedGoogle Scholar
  10. 10.
    Audo I, Michaelides M, Robson AG, Hawlina M, Vaclavik V, Sandbach JM, et al. Phenotypic variation in enhanced S-cone syndrome. Invest Ophthalmol Vis Sci. 2008;49:2082–93.CrossRefPubMedGoogle Scholar
  11. 11.
    Pachydaki SI, Klaver CC, Barbazetto IA, Roy MS, Gouras P, Allikmets R, et al. Phenotypic features of patients with NR2E3 mutations. Arch Ophthalmol. 2009;127:71–5.CrossRefPubMedGoogle Scholar
  12. 12.
    Bandah D, Merin S, Ashhab M, Banin E, Sharon D. The spectrum of retinal diseases caused by NR2E3 mutations in Israeli and Palestinian patients. Arch Ophthalmol. 2009;127:297–302.CrossRefPubMedGoogle Scholar
  13. 13.
    Genead MA, Fishman GA, McAnany JJ. Efficacy of topical dorzolamide for treatment of cystic macular lesions in a patient with enhanced S-cone syndrome. Doc Ophthalmol. 2010;121:231–40.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Rocha-Sousa A, Hayashi T, Gomes NL, Penas S, Brandão E, Rocha P, et al. A novel mutation (Cys83Tyr) in the second zinc finger of NR2E3 in enhanced S-cone syndrome. Graefes Arch Clin Exp Ophthalmol. 2011;249:201–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Cima I, Brecelj J, Sustar M, Coppieters F, Leroy BP, De Baere E, et al. Enhanced S-cone syndrome with preserved macular structure and severely depressed retinal function. Doc Ophthalmol. 2012;125:161–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Hull S, Arno G, Sergouniotis PI, Tiffin P, Borman AD, Chandra A, et al. Clinical and molecular characterization of enhanced S-cone syndrome in children. JAMA Ophthalmol. 2014;132:1341–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Hayashi T, Gekka T, Tsuneoka H. Spontaneous resolution of large macular retinoschisis in enhanced S-cone syndrome. Ophthalmic Surg Lasers Imaging Retina. 2016;47:187–90.CrossRefPubMedGoogle Scholar
  18. 18.
    Vaclavik V, Chakarova C, Bhattacharya SS, Robson AG, Holder GE, Bird AC, et al. Bilateral giant macular schisis in a patient with enhanced S-cone syndrome from a family showing pseudo-dominant inheritance. Br J Ophthalmol. 2008;92:299–300.CrossRefPubMedGoogle Scholar
  19. 19.
    Nakamura M, Hotta Y, Piao CH, Kondo M, Terasaki H, Miyake Y. Enhanced S-cone syndrome with subfoveal neovascularization. Am J Ophthalmol. 2002;133:575–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Lam BL, Goldberg JL, Hartley KL, Stone EM, Liu M. Atypical mild enhanced S-cone syndrome with novel compound heterozygosity of the NR2E3 gene. Am J Ophthalmol. 2007;144:157–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Hayashi T, Kitahara K. Optical coherence tomography in enhanced S-cone syndrome: large macular retinoschisis with disorganized retinal lamination. Eur J Ophthalmol. 2005;15:643–6.PubMedGoogle Scholar
  22. 22.
    Yzer S, Barbazetto I, Allikmets R, van Schooneveld MJ, Bergen A, Tsang SH, et al. Expanded clinical spectrum of enhanced S-cone syndrome. JAMA Ophthalmol. 2013;131:1324–30.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Arevalo JF, Kozak I. Enhanced S-cone syndrome and macular hole. JAMA Ophthalmol. 2015;133:e15108.CrossRefPubMedGoogle Scholar
  24. 24.
    Greenstein VC, Zaidi Q, Hood DC, Spehar B, Cideciyan AV, Jacobson SG. The enhanced S cone syndrome: an analysis of receptoral and post-receptoral changes. Vis Res. 1996;36:3711–22.CrossRefPubMedGoogle Scholar
  25. 25.
    Marmor MF, Tan F, Sutter EE, Bearse MA Jr. Topography of cone electrophysiology in the enhanced S cone syndrome. Invest Ophthalmol Vis Sci. 1999;40:1866–73.PubMedGoogle Scholar
  26. 26.
    Yamamoto S, Hayashi M, Takeuchi S. Electroretinograms and visual evoked potentials elicited by spectral stimuli in a patient with enhanced S-cone syndrome. Jpn J Ophthalmol. 1999;43:433–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Udar N, Small K, Chalukya M, Silva-Garcia R, Marmor M. Developmental or degenerative-NR2E3 gene mutations in two patients with enhanced S cone syndrome. Mol Vis. 2011;17:519–25.PubMedPubMedCentralGoogle Scholar
  28. 28.
    McCulloch DL, Marmor MF, Brigell MG, Hamilton R, Holder GE, Tzekov R, et al. ISCEV standard for full-field clinical electroretinography (2015 update). Doc Ophthalmol. 2015;130:1–12.CrossRefPubMedGoogle Scholar
  29. 29.
    Milam AH, Rose L, Cideciyan AV, Barakat MR, Tang WX, Gupta N, et al. The nuclear receptor NR2E3 plays a role in human retinal photoreceptor differentiation and degeneration. Proc Natl Acad Sci USA. 2002;99:473–8.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Ripamonti C, Aboshiha J, Henning GB, Sergouniotis PI, Michaelides M, Moore AT, et al. Vision in observers with enhanced S-cone syndrome: an excess of S-cones but connected mainly to conventional S-cone pathways. Invest Ophthalmol Vis Sci. 2014;55:963–76.CrossRefPubMedGoogle Scholar
  31. 31.
    Haider NB, Jacobson SG, Cideciyan AV, Swiderski R, Streb LM, Searby C, et al. Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nat Genet. 2000;24:127–31.CrossRefPubMedGoogle Scholar
  32. 32.
    Kobayashi M, Takezawa S, Hara K, Yu RT, Umesono Y, Agata K, et al. Identification of a photoreceptor cell-specific nuclear receptor. Proc Natl Acad Sci USA. 1999;96:4814–9.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Peng GH, 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 Mol Genet. 2005;14:747–64.CrossRefPubMedGoogle Scholar
  34. 34.
    Haider NB, Demarco P, Nystuen AM, Huang X, Smith RS, McCall MA, et al. The transcription factor Nr2e3 functions in retinal progenitors to suppress cone cell generation. Vis Neurosci. 2006;23:917–29.CrossRefPubMedGoogle Scholar
  35. 35.
    Jacobson SG, Sumaroka A, Aleman TS, Cideciyan AV, Schwartz SB, Roman AJ, et al. Nuclear receptor NR2E3 gene mutations distort human retinal laminar architecture and cause an unusual degeneration. Hum Mol Genet. 2004;13:1893–902.CrossRefPubMedGoogle Scholar
  36. 36.
    Sharon D, Sandberg MA, Caruso RC, Berson EL, Dryja TP. Shared mutations in NR2E3 in enhanced S-cone syndrome, Goldmann-Favre syndrome, and many cases of clumped pigmentary retinal degeneration. Arch Ophthalmol. 2003;121:1316–23.CrossRefPubMedGoogle Scholar
  37. 37.
    Gerber S, Rozet JM, Takezawa S, dos Santos LC, Lopes L, Gribouval O, et al. 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. 2000;107:276–84.CrossRefPubMedGoogle Scholar
  38. 38.
    Coppieters F, Leroy BP, Beysen D, Hellemans J, De Bosscher K, Haegeman G, et al. Recurrent mutation in the first zinc finger of the orphan nuclear receptor NR2E3 causes autosomal dominant retinitis pigmentosa. Am J Hum Genet. 2007;81:147–57.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Fishman GA, Jampol LM, Goldberg MF. Diagnostic features of the Favre-Goldmann syndrome. Br J Ophthalmol. 1976;60:345–53.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Jacobson SG, Román AJ, Román MI, Gass JDM, Parker JA. Relatively enhanced S cone function in the Goldmann-Favre syndrome. Am J Ophthalmol. 1991;111:446–53.CrossRefPubMedGoogle Scholar
  41. 41.
    Bonilha VL, Fishman GA, Rayborn ME, Hollyfield JG. Retinal pathology of a patient with Goldmann-Favre syndrome. Ophthalmic Genet. 2009;30:172–80.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Kuniyoshi K, Uno N, Irifune M, Shimomura Y. Electroretinography of short-wavelength-sensitive cones with a LED built-in electrode and its normal values. Doc Ophthalmol. 2003;106:311–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Mizunoya S, Kuniyoshi K, Arai M, Tahara K, Hirose T. Electroretinogram contact lens electrode with tri-color light-emitting diode. Acta Ophthalmol Scand. 2001;79:497–500.CrossRefPubMedGoogle Scholar
  44. 44.
    PolyPhen (polymorphism phenotyping). 2012. http://genetics.bwh.harvard.edu/pph/data/. Accessed 29 Apr 2016.
  45. 45.
    PolyPhen-2 (polymorphism phenotyping v2). 2016. http://genetics.bwh.harvard.edu/pph2/. Accessed 29 Apr 2016.
  46. 46.
    SIFT. 2011. http://sift.jcvi.org/. Accessed 29 Apr 2016.
  47. 47.
    Align GVGD. In: International Agency for Research on Cancer, World Health Organization. 2016. http://agvgd.iarc.fr/. Accessed 29 Apr 2016.
  48. 48.
    LOVD v3.0 (Leiden Open Variation Database). 2016. http://www.lovd.nl/3.0/home. Accessed 29 Apr 2016.
  49. 49.
    National Center for Biotechnology Information (NCBI). 2016. http://www.ncbi.nlm.nih.gov/. Accessed 29 Apr 2016.
  50. 50.
    Human Gene Mutation Database (HGMD). 2016. https://www.qiagenbioinformatics.com/products/human-gene-mutation-database/. Accessed 29 Apr 2016.
  51. 51.
    Human Genetic Variation Database (HGVD). 2016. http://www.genome.med.kyoto-u.ac.jp/SnpDB/. Accessed 29 Apr 2016.

Copyright information

© Japanese Ophthalmological Society 2016

Authors and Affiliations

  • Kazuki Kuniyoshi
    • 1
    Email author
  • Takaaki Hayashi
    • 2
  • Hiroyuki Sakuramoto
    • 1
  • Hiroshi Mishima
    • 1
  • Hiroshi Tsuneoka
    • 2
  • Kazushige Tsunoda
    • 3
  • Takeshi Iwata
    • 4
  • Yoshikazu Shimomura
    • 1
  1. 1.Department of OphthalmologyKinki University Faculty of MedicineOsaka-SayamaJapan
  2. 2.Department of OphthalmologyThe Jikei University School of MedicineTokyoJapan
  3. 3.Laboratory of Visual Physiology, National Institute of Sensory OrgansNational Hospital Organization Tokyo Medical CenterTokyoJapan
  4. 4.Division of Molecular and Cellular Biology, National Institute of Sensory OrgansNational Hospital Organization Tokyo Medical CenterTokyoJapan

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