Documenta Ophthalmologica

, Volume 131, Issue 1, pp 71–79 | Cite as

Reduced rod electroretinograms in carrier parents of two Japanese siblings with autosomal recessive retinitis pigmentosa associated with PDE6B gene mutations

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



To present the clinical and genetic findings in two siblings with autosomal recessive retinitis pigmentosa (RP) and their non-symptomatic parents.


We studied two siblings, a 48-year-old woman and her 44-year-old brother, and their parents. They had general ophthalmic examinations including ophthalmoscopy, perimetry, and electroretinography (ERG). Their whole exomes were analyzed by the next-generation sequence technique.


The two siblings had night blindness for a long time, and clinical examinations revealed diffuse retinal degeneration with bone spicule pigmentation, constriction of the visual field, and non-recordable ERGs. Their parents were non-symptomatic and had normal fundi; however, their rod ERGs were reduced. Genetic examination revealed compound heterozygous mutations of I535N and H557Y in the PDE6B gene in the siblings, and the parents were heterozygous carriers of the mutations.


Heterozygous mutation in the PDE6B gene can cause a reduction in the rod function to different degrees. The retinal function of non-symptomatic carriers of autosomal recessive RP should be evaluated with care.


PDE6B Retinitis pigmentosa Congenital stationary night blindness Electroretinograms Carrier Autosomal recessive Japanese 



The authors thank Professor Duco Hamasaki of the Bascom Palmer Eye Institute of the University of Miami for critical discussion and final manuscript revisions; Miss Seiko Kawamura, CO, of the Seichokai Fuchu Hospital (Osaka, Japan); and Mr. Tomoaki Nishio of TOMEY Corporation (Nagoya, Japan) for their assistance for ERG examinations. The authors wish to acknowledge RIKEN GeNAS for the sequencing of the exome-enriched libraries. This research was supported by the research grants to T.I., K.T., and K.K. from the Ministry of Health, Labour and Welfare, Japan (13803661), to K.T. and K.K. from the Ministry of Health, Labour and Welfare, Japan (23164001), Y.S from the Ministry of Health, Labour and Welfare, Japan (82259921), 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 Omics Science Center.

Conflict of interest

All authors have no commercial interests related to this research.


  1. 1.
    Weleber RG, Gregory-Evans K (2006) Retinitis pigmentosa and allied disorders. In: Hinton DR (ed), Ryan SJ (ed in chief) Retina, 4th edn, vol 1. Elsevier Inc., Philadelphia, pp 395–498Google Scholar
  2. 2.
    Heckenlively JR (1988) Retinitis pigmentosa. J.B. Lippincott Company, Philadelphia, pp 1–24Google Scholar
  3. 3.
    Daiger SP, The University of Texas-Houston Health Science Center (2015) RetNet™. Retinal information network. Updated February 19, 2015. Accessed 1 Mar 2015
  4. 4.
    Weber B, Riess O, Hutchinson G, Collins C, Lin B, Kowbel D, Andrew S, Schappert K, Hayden MR (1991) Genomic organization and complete sequence of the human gene encoding the β-subunit of the cGMP phosphodiesterase and its localisation to 4p16.3. Nucleic Acids Res 19:6263–6268PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    McLaughlin ME, Sandberg MA, Berson EL, Dryja TP (1993) Recessive mutations in the gene encoding the β-subunit of rod phosphodiesterase in patients with retinitis pigmentosa. Nat Genet 4:130–134PubMedCrossRefGoogle Scholar
  6. 6.
    Bayés M, Giordano M, Balcells S, Grinberg D, Vilageliu L, Martínez I, Ayuso C, Benítez J, Ramos-Arroyo MA, Chivelet P, Solans T, Valverde D, Amselem S, Goossens M, Baiget M, Gonzàlez-Duarte R, Besmond C (1995) Homozygous tandem duplication within the gene encoding the β-subunit of rod phosphodiesterase as a cause for autosomal recessive retinitis pigmentosa. Hum Mutat 5:228–234PubMedCrossRefGoogle Scholar
  7. 7.
    McLaughlin ME, Ehrhart TL, Berson EL, Dryja TP (1995) Mutation spectrum of the gene encoding the β subunit of rod phosphodiesterase among patients with autosomal recessive retinitis pigmentosa. Proc Natl Acad Sci USA 92:3249–3253PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Danciger M, Blaney J, Gao YQ, Zhao DY, Heckenlively JR, Jacobson SG, Farber DB (1995) Mutations in the PDE6B gene in autosomal recessive retinitis pigmentosa. Genomics 30:1–7PubMedCrossRefGoogle Scholar
  9. 9.
    Valverde D, Solans T, Grinberg D, Balcells S, Vilageliu L, Bayés M, Chivelet P, Besmond C, Goossens M, González-Duarte R, Baiget M (1996) A novel mutation in exon 17 of the β-subunit of rod phosphodiesterase in two RP sisters of a consanguineous family. Hum Genet 97:35–38PubMedCrossRefGoogle Scholar
  10. 10.
    Danciger M, Heilbron V, Gao YQ, Zhao DY, Jacobson SG, Farber DB (1996) A homozygous PDE6B mutation in a family with autosomal recessive retinitis pigmentosa. Mol Vis 2:10PubMedGoogle Scholar
  11. 11.
    Valvelde D, Baiget M, Seminago R, del Rio E, García-Sandoval B, del Rio T, Bayés M, Balcells S, Martínez A, Grinberg D, Ayuso C (1996) Identification of a novel R552Q mutation in exon 13 of the β-subunit of rod phosphodiesterase gene in a Spanish family with autosomal recessive retinitis pigmentosa. Hum Mutat 8:393–394CrossRefGoogle Scholar
  12. 12.
    Saga M, Mashima Y, Akeo K, Kudoh J, Oguchi Y, Shimizu N (1998) A novel homozygous Ile535Asn mutation in the rod cGMP phosphodiesterase β-subunit gene in two brothers of a Japanese family with autosomal recessive retinitis pigmentosa. Curr Eye Res 17:332–335PubMedCrossRefGoogle Scholar
  13. 13.
    Jin ZB, Mandai M, Yokota T, Higuchi K, Ohmori K, Ohtsuki F, Takakura S, Itabashi T, Wada Y, Akimoto M, Ooto S, Suzuki T, Hirami Y, Ikeda H, Kawagoe N, Oishi A, Ichiyama S, Takahashi M, Yoshimura N, Kosugi S (2008) Identifying pathogenic genetic background of simplex or multiplex retinitis pigmentosa patients: a large scale mutation screening study. J Med Genet 45:465–472PubMedCrossRefGoogle Scholar
  14. 14.
    Tsang SH, Tsui I, Chou CL, Zernant J, Haamer E, Iranmanesh R, Tosi J, Allikmets R (2008) A novel mutation and phenotypes in phosphodiesterase 6 deficiency. Am J Ophthalmol 146:780–788PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Hmani-Aifa M, Benzina Z, Zulfiqar F, Dhouib H, Shahzadi A, Ghorbel A, Rebaï A, Söderkvist P, Riazuddin S, Kimberling WJ, Ayadi H (2009) Identification of two new mutations in the GPR98 and the PDE6B genes segregating in a Tunisian family. Eur J Hum Genet 17:474–482PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Ali S, Riazuddin SA, Shahzadi A, Nasir IA, Khan SN, Husnain T, Akram J, Sieving PA, Hejtmancik JF, Riazuddin S (2011) Mutations in the β-subunit of rod phosphodiesterase identified in consanguineous Pakistani families with autosomal recessive retinitis pigmentosa. Mol Vis 17:1373–1380PubMedCentralPubMedGoogle Scholar
  17. 17.
    Neveling K, Collin RWJ, Gilissen C, van Huet RAC, Visser L, Kwint MP, Gijsen SJ, Zonneveld MN, Wieskamp N, de Ligt J, Siemiatkowska AM, Hoefsloot LH, Buckley MF, Kellner U, Branham KE, den Hollander AI, Hoischen A, Hoyng C, Klevering BJ, van den Born LI, Veltman JA, Cremers FPM, Scheffer H (2012) Next-generation genetic testing for retinitis pigmentosa. Hum Mutat 33:963–972PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Kim C, Kim KJ, Bok J, Lee EJ, Kim DJ, Oh JH, Park SP, Shin JY, Lee JY, Yu HG (2012) Microarray-based mutation detection and phenotypic characterization in Korean patients with retinitis pigmentosa. Mol Vis 18:2398–2410PubMedCentralPubMedGoogle Scholar
  19. 19.
    Bocquet B, Na Marzouka, Hebrard M, Manes G, Sénéchal A, Meunier I, Hamel CP (2013) Homozygosity mapping in autosomal recessive retinitis pigmentosa families detects novel mutations. Mol Vis 19:2487–2500PubMedCentralPubMedGoogle Scholar
  20. 20.
    Shen S, Sujirakul T, Tsang SH (2014) Next-generation sequencing revealed a novel mutation in the gene encoding the beta subunit of rod phosphodiesterase. Ophthalmic Genet 35:142–150PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Gross AK, Wensel TG (2011) Biochemical cascade of phototransduction. In: Levin LA, Nilsson SFE, Ver Hoeve J, Wu SM (eds) Adler’s physiology of the eye, 11th edn. Elsevier Inc, Edinburgh, pp 394–410CrossRefGoogle Scholar
  22. 22.
    Bowes C, Li T, Danciger M, Baxter LC, Applebury ML, Farber DB (1990) Retinal degeneration in the rd mouse is caused by a defect in the β subunit of rod cGMP-phosphodiesterase. Nature 347:677–680PubMedCrossRefGoogle Scholar
  23. 23.
    Davis RJ, Tosi J, Janisch KM, Kasanuki JM, Wang NK, Kong J, Tsui I, Cilluffo M, Woodruff ML, Fain GL, Lin CS, Tsang SH (2008) Functional rescue of degenerating photoreceptors in mice homozygous for a hypomorphic cGMP phosphodiesterase 6 b allele (Pde6b H620Q). Investig Ophthalmol Vis Sci 49:5067–5076CrossRefGoogle Scholar
  24. 24.
    Pang JJ, Boye SL, Kumar A, Dinculescu A, Deng W, Li J, Li Q, Rani A, Foster TC, Chang B, Hawes NL, Boatright JH, Hauswirth WW (2008) AAV-mediated gene therapy for retinal degeneration in the rd10 mouse containing a recessive PDEβ mutation. Investig Ophthalmol Vis Sci 49:4278–4283CrossRefGoogle Scholar
  25. 25.
    Allocca M, Manfredi A, Iodice C, Di Vicino U, Auricchio A (2011) AAV-mediated gene replacement, either alone or in combination with physical and pharmacological agents, results in partial and transient protection from photoreceptor degeneration associated with βPDE deficiency. Investig Ophthalmol Vis Sci 52:5713–5719CrossRefGoogle Scholar
  26. 26.
    Barabas P, Peck CC, Krizaj D (2010) Do calcium channel blockers rescue dying photoreceptors in the Pde6b rd1 mouse? Adv Exp Med Biol 664:491–499PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    McCulloch DL, Marmor MF, Brigell MG, Hamilton R, Holder GE, Tzekov R, Bach M (2015) ISCEV Standard for full-field clinical electroretinography (2015 update). Doc Ophthalmol 130:1–12PubMedCrossRefGoogle Scholar
  28. 28.
    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
  29. 29.
    Adzhubei I, Jordan DM, Sunyaev SR (2013) Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet 76:7.20.1-7.20.41Google Scholar
  30. 30.
    National Institute of Genetics (NIG) (2014) Cell Innovation Program. Accessed 1 Mar 2015
  31. 31.
    Kyoto University (2014) Human Genetic Variation Browser. Accessed 1 Mar 2015
  32. 32.
    Rambusch SHA (1909) Den medfødte Natteblindheds Arvelighedsforhold. Oversigt over det Kgl. Danske Videnskabernes Selskabs Forhandlinger 3:337–347Google Scholar
  33. 33.
    Gal A, Orth U, Baehr W, Schwinger E, Rosenberg T (1994) Heterozygous missense mutation in the rod cGMP phosphodiesterase β-subunit gene in autosomal dominant stationary night blindness. Nat Genet 7:64–68PubMedCrossRefGoogle Scholar
  34. 34.
    Tsang SH, Woodruff ML, Jun L, Mahajan V, Yamashita CK, Pedersen R, Lin CS, Goff SP, Rosenberg T, Larsen M, Farber DB, Nusinowitz S (2007) Transgenic mice carrying the H258N mutation in the gene encoding the β-subunit of phosphodiesterase-6 (PDE6B) provide a model for human congenital stationary night blindness. Hum Mutat 28:243–254PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Manes G, Cheguru P, Majumder A, Bocquet B, Sénéchal A, Artemyev NO, Hamel CP, Brabet P (2014) A truncated form of rod photoreceptor PDE6 β-subunit causes autosomal dominant congenital stationary night blindness by interfering with the inhibitory activity of the γ-subunit. PLoS One 9:e95768PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Kazuki Kuniyoshi
    • 1
  • Hiroyuki Sakuramoto
    • 1
  • Kazutoshi Yoshitake
    • 2
  • Kazuho Ikeo
    • 2
  • Masaaki Furuno
    • 3
  • Kazushige Tsunoda
    • 4
  • Shunji Kusaka
    • 5
  • Yoshikazu Shimomura
    • 1
  • Takeshi Iwata
    • 6
  1. 1.Department of OphthalmologyKinki University Faculty of MedicineOsakaJapan
  2. 2.Laboratory for DNA Data AnalysisNational Institute of GeneticsShizuokaJapan
  3. 3.Division of Genomic Technologies, Life Science Accelerator Technology Group, Transcriptome Technology TeamRIKEN Center for Life Science TechnologiesYokohamaJapan
  4. 4.Laboratory of Visual Physiology, National Institute of Sensory OrgansNational Hospital Organization Tokyo Medical CenterTokyoJapan
  5. 5.Department of Ophthalmology, Sakai HospitalKinki University Faculty of MedicineOsakaJapan
  6. 6.Division of Molecular and Cellular Biology, National Institute of Sensory OrgansNational Hospital Organization Tokyo Medical CenterTokyoJapan

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