Documenta Ophthalmologica

, Volume 130, Issue 1, pp 49–55 | Cite as

Novel nonsense and splice site mutations in CRB1 gene in two Japanese patients with early-onset retinal dystrophy

  • Kazuki Kuniyoshi
  • Kazuho Ikeo
  • Hiroyuki Sakuramoto
  • Masaaki Furuno
  • Kazutoshi Yoshitake
  • Yoshikazu Hatsukawa
  • Akira Nakao
  • Kazushige Tsunoda
  • Shunji Kusaka
  • Yoshikazu Shimomura
  • Takeshi Iwata
Clinical Case Report



To report novel mutations in the CRB1 gene in two patients with early-onset retinal dystrophy (EORD) and the longitudinal clinical course of EORD.

Patients and methods

The patients were two unrelated Japanese children. Standard ophthalmic examinations including perimetry, electroretinography, and optical coherence tomography were performed on both patients. Whole exomes of the patients and their nonsymptomatic parents were analyzed using a next-generation sequence (NGS) technique.


Patient 1 was noted to have esotropia and hyperopia at age 3. His decimal best-corrected visual acuity (BCVA) was 0.6 OD and 0.3 OS at age 6 with de-pigmentation of the retinal pigment epithelium (RPE). At age 19, his central vision was still preserved; however, numerous pigment granules were present in the retina. NGS analysis revealed a p.R632X nonsense and c.652 + 1_652 + 4delGTAA splice site mutations in the CRB1 gene. Patient 2 was noted to have hyperopia at age 3. His decimal BCVA at age 6 was 0.3 OD and 0.4 OS with de-pigmented RPE. The degree of retinal pigmentation was increased but his BCVA was good until the age of 14 years. NGS analysis revealed c.652 + 1_652 + 4delGTAA and c.652 + 1_652 + 2insT splice site mutations in the CRB1 gene.


The phenotypes of these novel mutations for EORD are typical of CRB1-associated EORD (LCA8). They were slowly progressive until the second decade of life.


Leber congenital amaurosis Early-onset retinal dystrophy CRB1 Optical coherence tomography Electroretinography Visual fields Japanese 



This research was supported by the research Grants to T.I., K.T., Y.S., and K.K. from the Ministry of Health, Labour and Welfare, Japan (13803661, 23164001, and 82259921), to S.K. and K.K. from Japan Society for the Promotion of Science, Japan (23592597), and to M.F. from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) for RIKEN Center for Life Science Technologies.


  1. 1.
    Leber T (1869) Ueber Retinitis pigmentosa und angeborene Amaurose. Graefes Arch Klin Exp Ophthalmol 15:1–25CrossRefGoogle Scholar
  2. 2.
    Leber T (1916) Die Pigmentdegeneration der Netzhaut und die mit ihr verwandten Erkrankungen. In: Saemisch T, Elschnig A (eds) Graefe-Saemisch-Hess Handbuch der gesamten Augenheilkunde. Verlag von Wilherm Engelmann, Leipzig, Zweite Hälfte, pp 1076–1225Google Scholar
  3. 3.
    Weleber RG, Gregory-Evans K (2006) Leber congenital amaurosis. In: Hinton DR (ed), Ryan SJ (ed in chief) Retina, 4th edn, vol. 1. Elsevier, Philadelphia, pp 455–457Google Scholar
  4. 4.
    Daiger SP, The University of Texas Health Science Center (2014) RetNet™. Retinal information network. Updated September 11, 2014. Accessed 30 Sept 2014
  5. 5.
    Weleber RG, Francis PJ, Trzupek KM, Beattie C (2013) Leber congenital amaurosis. In: Pagon RA (ed in chief). GeneReviews®. NCBI Bookshelf. Accessed 30 Sept 2014
  6. 6.
    Lotery AJ, Jacobson SG, Fishman GA, Weleber RG, Fulton AB, Namperumalsamy P, Héon E, Levin AV, Grover S, Rosenow JR, Kopp KK, Sheffield VC, Stone EM (2001) Mutations in the CRB1 gene cause Leber congenital amaurosis. Arch Ophthalmol 119:415–420PubMedCrossRefGoogle Scholar
  7. 7.
    den Hollander Al, Davis J, van der Velde-Visser SD, Zonneveld MN, Pierrottet CO, Koenekoop RK, Kellner U, van den Born LI, Heckenlively JR, Hoyng CB, Handford PA, Roepman R, Cremers FPM (2004) CRB1 mutation spectrum in inherited retinal dystrophies. Hum Mutat 24:355–369CrossRefGoogle Scholar
  8. 8.
    Hanein S, Perrault I, Gerber S, Tanguy G, Barbet F, Ducroq D, Calvas P, Dollfus H, Hamel C, Lopponen T, Munier F, Santos L, Shalev S, Zafeiriou D, Dufier JL, Munnich A, Rozet JM, Kaplan J (2004) Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis. Hum Mutat 23:306–317PubMedCrossRefGoogle Scholar
  9. 9.
    Henderson RH, Mackay DS, Li Z, Moradi P, Sergouniotis P, Russell-Eggitt I, Thompson DA, Robson AG, Holder GE, Webster AR, Moore AT (2011) Phenotypic variability in patients with retinal dystrophies due to mutations in CRB1. Br J Ophthalmol 95:811–817PubMedCrossRefGoogle Scholar
  10. 10.
    den Hollander AI, ten Brink JB, de Kok YJM, van Soest S, van den Born LI, van Driel MA, van de Pol DJR, Payne AM, Bhattacharya SS, Kellner U, Hoyng CB, Westerveld A, Brunner HG, Bleeker-Wagemakers EM, Deutman AF, Heckenlively JR, Cremers FPM, Bergen AAB (1999) Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12). Nat Genet 23:217–221CrossRefGoogle Scholar
  11. 11.
    den Hollander AI, Heckenlively JR, van den Born LI, de Kok YJM, van der Velde-Visser SD, Kellner U, Jurklies B, van Schooneveld MJ, Blankenagel A, Rohrschneider K, Wissinger B, Cruysberg JRM, Deutman AF, Brunner HG, Apfelstedt-Sylla E, Hoyng CB, Cremers FPM (2001) Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene. Am J Hum Genet 69:198–203PubMedCentralCrossRefGoogle Scholar
  12. 12.
    Bernal S, Calaf M, Garcia-Hoyos M, Garcia-Sandoval B, Rosell J, Adan A, Ayuso C, Baiget M (2003) Study of the involvement of the RGR, CRPB1, and CRB1 genes in the pathogenesis of autosomal recessive retinitis pigmentosa. J Med Genet 40:e89PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Marmor MF, Fulton AB, Holder GE, Miyake Y, Brigell M, Bach M (2009) ISCEV Standard for full-field clinical electroretinography (2008 update). Doc Ophthalmol 118:69–77PubMedCrossRefGoogle Scholar
  14. 14.
    Kuniyoshi K, Sakuramoto H, Yoshitake K, Abe K, Ikeo K, Furuno M, Tsunoda K, Kusaka S, Shimomura Y, Iwata T (2014) Longitudinal clinical course of three Japanese patients with Leber congenital amaurosis/early-onset retinal dystrophy with RDH12 mutation. Doc Ophthalmol 128:219–228PubMedCrossRefGoogle Scholar
  15. 15.
    Pellikka M, Tanentzapf G, Pinto M, Smith C, McGlade CJ, Ready DF, Tepass U (2002) Crumbs, the Drosophila homologue of human CRB1/RP12, is essential for photoreceptor morphogenesis. Nature 416:143–149PubMedCrossRefGoogle Scholar
  16. 16.
    Jacobson SG, Cideciyan AV, Aleman TS, Pianta MJ, Sumaroka A, Schwartz SB, Smilko EE, Milam AH, Sheffield VC, Stone EM (2003) Crumbs homolog 1 (CRB1) mutations result in a thick human retina with abnormal lamination. Hum Mol Genet 12:1073–1078PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Kazuki Kuniyoshi
    • 1
  • Kazuho Ikeo
    • 2
  • Hiroyuki Sakuramoto
    • 1
  • Masaaki Furuno
    • 3
  • Kazutoshi Yoshitake
    • 2
  • Yoshikazu Hatsukawa
    • 4
  • Akira Nakao
    • 1
  • Kazushige Tsunoda
    • 5
  • Shunji Kusaka
    • 6
  • Yoshikazu Shimomura
    • 1
  • Takeshi Iwata
    • 7
  1. 1.Department of OphthalmologyKinki University Faculty of MedicineOsaka-Sayama CityJapan
  2. 2.Laboratory of DNA Data AnalysisNational Institute of GeneticsShizuokaJapan
  3. 3.Transcriptome Technology Team, Life Science Accelerator Technology Group, Division of Genomic TechnologiesRIKEN Center for Life Science TechnologiesYokohamaJapan
  4. 4.Department of OphthalmologyOsaka Medical Center and Research Institute for Maternal and Child HealthOsakaJapan
  5. 5.Laboratory of Visual Physiology, National Institute of Sensory OrgansNational Hospital Organization Tokyo Medical CenterTokyoJapan
  6. 6.Department of Ophthalmology, Sakai HospitalKinki University Faculty of MedicineOsakaJapan
  7. 7.Division of Molecular and Cellular Biology, National Institute of Sensory OrgansNational Hospital Organization Tokyo Medical CenterTokyoJapan

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