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Compound heterozygous CNGA3 mutations (R436W, L633P) in a Japanese patient with congenital achromatopsia

Published online by Cambridge University Press:  06 September 2006

SATOSHI GOTO-OMOTO ,
TAKAAKI HAYASHI ,
TAMAKI GEKKA ,
AKIKO KUBO ,
TOMOKAZU TAKEUCHI  and
KENJI KITAHARA
SATOSHI GOTO-OMOTO
Affiliation:
Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan
TAKAAKI HAYASHI
Affiliation:
Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan
TAMAKI GEKKA
Affiliation:
Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan
AKIKO KUBO
Affiliation:
Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan
TOMOKAZU TAKEUCHI
Affiliation:
Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan
KENJI KITAHARA
Affiliation:
Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan
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Abstract

Congenital achromatopsia is a stationary retinal disorder with autosomal recessive inheritance that is characterized by loss of color discrimination, low visual acuity, photophobia, and nystagmus. This disorder has been shown to be associated with CNGA3, CNGB3, and GNAT2 mutations, and the frequency of mutations in the CNGA3 gene (encoding α subunit of the cone-specific cGMP-gated cation channel) was 23–33% in European populations. The aim of this study was to test the hypothesis that CNGA3 mutations are also responsible for congenital achromatopsia in Japanese patients. DNA from venous blood samples from a total of 14 patients from 13 Japanese pedigrees was prepared. Mutation screening of the CNGA3 gene was performed using direct sequencing and PCR-single-strand conformation polymorphism analysis. Compound heterozygous missense mutations (p.R436W and p.L633P, the latter of which was novel) were identified in one patient only, a 22-year-old female. Neither of these two mutations was found in 150 Japanese control individuals. The patient's parents and sister carried one of these mutations each but were not affected. No mutations in the CNGB3 or GNAT2 genes were identified in the patient. Clinically, best-corrected visual acuity was 0.1 in both eyes. No specific findings were obtained in funduscopy. Optical coherence topography revealed a normal foveal thickness but a 20% decrease in parafoveal thickness. Ganzfeld full-field electroretinograms (ERGs) showed normal responses in rod and mixed rod-plus-cone ERGs but no response in cone or 30-Hz flicker ERGs. Spectral sensitivity on a white background revealed a curve with only one peak at around 500 nm, which fits the absorption spectrum of human rhodopsin. L633, conserved among vertebrate orthologs of human CNGA3, is a hydrophobic residue forming part of the carboxy-terminal leucine zipper (CLZ) domain, which is functionally important in the mediation of intracellular interactions. To our knowledge, this is the first report of a Japanese complete achromat with CNGA3 mutations, and of any patient with a missense mutation within the CLZ domain. The outcome suggests low frequency (7%, 1/14) of CNGA3 mutations in Japanese patients.

Keywords

Color vision deficiencyAchromatopsiaCNGA3MutationGenetics
Type
GENETICS
Information
Visual Neuroscience , Volume 23 , Issue 3-4 , May 2006 , pp. 395 - 402
Copyright
© 2006 Cambridge University Press

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References

REFERENCES

Aligianis, I.A., Forshew, T., Johnson, S., Michaelides, M., Johnson, C.A., Trembath, R.C., Hunt, D.M., Moore, A.T., & Maher, E.R. (2002). Mapping of a novel locus for achromatopsia (ACHM4) to 1p and identification of a germline mutation in the alpha subunit of cone transducin (GNAT2). Journal of Medical Genetics 39, 656–660.CrossRefGoogle Scholar
Alpern, M., Falls, H.F., & Lee, G.B. (1960). The enigma of typical total monochromacy. American Journal of Ophthalmology 50, 326–342.CrossRefGoogle Scholar
Antonarakis, S.E. (1998). Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group. Human Mutation 11, 1–3.Google Scholar
Blackwell, H.R. & Blackwell, O.M. (1961). Rod and cone receptor mechanisms in typical and atypical congenital achromatopsia. Vision Research 1, 62–107.CrossRefGoogle Scholar
Bönigk, W., Altenhofen, W., Müller, F., Dose, A., Illing, M., Molday, R.S., & Kaupp, U.B. (1993). Rod and cone photoreceptor cells express distinct genes for cGMP-gated channels. Neuron 10, 865–877.CrossRefGoogle Scholar
Crescitelli, F. & Dartnall, H.J. (1953). Human visual purple. Nature 172, 195–197.CrossRefGoogle Scholar
Deeb, S.S. & Kohl, S. (2003). Genetics of color vision deficiencies. In Genetics in Opthalmology. Dev Ophthalmol., eds. Wissinger, B., Kohl, S. & Langenbeck, U., pp. 170–187. Switzerland: Basel, Karger.CrossRef
den Dunnen, J.T. & Antonarakis, S.E. (2000). Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Human Mutation 15, 7–12.3.0.CO;2-N>CrossRefGoogle Scholar
Eksandh, L., Kohl, S., & Wissinger, B. (2002). Clinical features of achromatopsia in Swedish patients with defined genotypes. Ophthalmic Genetics 23, 109–120.CrossRefGoogle Scholar
Goodman, G., Ripps, M., & Siegel, I.M. (1963). Cone dysfunction syndromes. Archives of Ophthalmology 70, 214–231.CrossRefGoogle Scholar
Hayashi, T., Kozaki, K., Kitahara, K., Kubo, A., Nishio, Y., Omoto, S., Nakamura, Y., Watanabe, A., Toda, K., & Ueoka, Y. (2004a). Clinical heterogeneity between two Japanese siblings with congenital achromatopsia. Visual Neuroscience 21, 413–420.Google Scholar
Hayashi, T., Omoto, S., Takeuchi, T., Kozaki, K., Ueoka, Y., & Kitahara, K. (2004b). Four Japanese male patients with juvenile retinoschisis: Only three have mutations in the RS1 gene. American Journal of Ophthalmology 138, 788–798.Google Scholar
Jägle, H., Kohl, S., Apfelstedt-Sylla, E., Wissinger, B., & Sharpe, L.T. (2001). Manifestations of rod monochromacy. Color Research and Application 26, S96–S99.3.0.CO;2-L>CrossRefGoogle Scholar
Johnson, S., Michaelides, M., Aligianis, I.A., Ainsworth, J.R., Mollon, J.D., Maher, E.R., Moore, A.T., & Hunt, D.M. (2004). Achromatopsia caused by novel mutations in both CNGA3 and CNGB3. Journal of Medical Genetics 41, e20.CrossRefGoogle Scholar
Kandatsu, A. & Kitahara, K. (1993). The visual characteristics of a case of Pigmentfarbenanomalie. In Colour Vision Deficiencies XI, ed. Drum, B., pp. 113–117. Netherlands: Kluwer Academic Publishers.CrossRef
Kohl, S., Baumann, B., Broghammer, M., Jägle, H., Sieving, P., Kellner, U., Spegal, R., Anastasi, M., Zrenner, E., Sharpe, L.T., & Wissinger, B. (2000). Mutations in the CNGB3 gene encoding the beta-subunit of the cone photoreceptor cGMP-gated channel are responsible for achromatopsia (ACHM3) linked to chromosome 8q21. Human Molecular Genetics 9, 2107–2116.CrossRefGoogle Scholar
Kohl, S., Baumann, B., Rosenberg, T., Kellner, U., Lorenz, B., Vadalà, M., Jacobson, S.G., & Wissinger, B. (2002). Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia. American Journal of Human Genetics 71, 422–425.CrossRefGoogle Scholar
Kohl, S., Marx, T., Giddings, I., Jägle, H., Jacobson, S.G., Apfelstedt-Sylla, E., Zrenner, E., Sharpe, L.T., & Wissinger, B. (1998). Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nature Genetics 19, 257–259.Google Scholar
Kohl, S., Varsanyi, B., Antunes, G.A., Baumann, B., Hoyng, C.B., Jägle, H., Rosenberg, T., Kellner, U., Lorenz, B., Salati, R., Jurklies, B., Farkas, A., Andreasson, S., Weleber, R.G., Jacobson, S.G., Rudolph, G., Castellan, C., Dollfus, H., Legius, E., Anastasi, M., Bitoun, P., Lev, D., Sieving, P.A., Munier, F.L., Zrenner, E., Sharpe, L.T., Cremers, F.P., & Wissinger, B. (2005). CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia. European Journal of Human Genetics 13, 302–308.CrossRefGoogle Scholar
Krill, A.E., Deutman, A.F., & Fishman, M. (1973). The cone degenerations. Documenta Ophthalmologica 35, 1–80.CrossRefGoogle Scholar
Krill, A.E., Smith, V.C., & Pokorny, J. (1971). Further studies supporting the identity of congenital tritanopia and hereditary dominant optic atrophy. Investigative Ophthalmology 10, 457–465.Google Scholar
Michaelides, M., Aligianis, I.A., Ainsworth, J.R., Good, P., Mollon, J.D., Maher, E.R., Moore, A.T., & Hunt, D.M. (2004). Progressive cone dystrophy associated with mutation in CNGB3. Investigative Ophthalmology and Visual Science 45, 1975–1982.CrossRefGoogle Scholar
Michaelides, M., Aligianis, I.A., Holder, G.E., Simunovic, M., Mollon, J.D., Maher, E.R., Hunt, D.M., & Moore, A.T. (2003). Cone dystrophy phenotype associated with a frameshift mutation (M280fsX291) in the alpha-subunit of cone specific transducin (GNAT2). British Journal of Ophthalmology 87, 1317–1320.CrossRefGoogle Scholar
Nakamura, Y., Hayashi, T., Kozaki, K., Kubo, A., Omoto, S., Watanabe, A., Toda, K., Takeuchi, T., Gekka, T., & Kitahara, K. (2004). Enhanced S-cone syndrome in a Japanese family with a nonsense NR2E3 mutation (Q350X). Acta Ophthalmologica Scandinavica 82, 616–622.CrossRefGoogle Scholar
Nishiguchi, K.M., Sandberg, M.A., Gorji, N., Berson, E.L., & Dryja, T.P. (2005). Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases. Human Mutation 25, 248–258.CrossRefGoogle Scholar
Niwa, T., Terasaki, H., Kondo, M., Piao, C.H., Suzuki, T., & Miyake, Y. (2003). Function and morphology of macula before and after removal of idiopathic epiretinal membrane. Investigative Ophthalmology and Visual Science 44, 1652–1656.CrossRefGoogle Scholar
Okada, A., Ueyama, H., Oda, S., Tanaka, Y., Tanabe, S., & Yamade, S. (2001). Analysis of CNGA3 and CNGB3 genes in Japanese patients with rod monochromacy. Investigative Ophthalmology and Visual Science 42, S639.Google Scholar
Okada, A., Ueyama, H., Toyoda, F., Oda, S., Ding, W.G., Tanabe, S., Yamade, S., Matsuura, H., Ohkubo, I., & Kani, K. (2004). Functional role of hCngb3 in regulation of human cone cng channel: Effect of rod monochromacy-associated mutations in hCNGB3 on channel function. Investigative Ophthalmology and Visual Science 45, 2324–2332.CrossRefGoogle Scholar
Peng, C., Rich, E.D., & Varnum, M.D. (2004). Subunit configuration of heteromeric cone cyclic nucleotide-gated channels. Neuron 42, 401–410.CrossRefGoogle Scholar
Sharpe, L.T., Stockman, A., Jägle, H., & Nathans, J. (1999). Opsin genes, cone photopigments, color vision, and color blindness. In Color Vision: From genes to perception, eds. Gegenfurtner, K. & Sharpe, L.T., pp. 3–52. Cambridge: Cambridge University Press.
Smith, V.C. & Pokorny, J. (1980). Cone dysfunction syndromes defined by colour vision. In Colour Vision Deficiencies V, ed. Verriest, G., pp. 69–82. Bristol: Adam Hilger.
Sundin, O.H., Yang, J.M., Li, Y., Zhu, D., Hurd, J.N., Mitchell, T.N., Silva, E.D., & Maumenee, I.H. (2000). Genetic basis of total colourblindness among the Pingelapese islanders. Nature Genetics 25, 289–293.CrossRefGoogle Scholar
Waardenburg, P. (1963). Achromatopsia congenita. In Genetics and Ophthalmology, vol. II, eds. Waardenburg, P., Franceschetti, A. & Klein, D., pp. 1695–1718. Assen, Netherlands: Royal van Gorcum.
Wald, G. & Brown, P.K. (1958). Human rhodopsin. Science 127, 222–226.CrossRefGoogle Scholar
Wissinger, B., Gamer, D., Jägle, H., Giorda, R., Marx, T., Mayer, S., Tippmann, S., Broghammer, M., Jurklies, B., Rosenberg, T., Jacobson, S.G., Sener, E.C., Tatlipinar, S., Hoyng, C.B., Castellan, C., Bitoun, P., Andreasson, S., Rudolph, G., Kellner, U., Lorenz, B., Wolff, G., Verellen-Dumoulin, C., Schwartz, M., Cremers, F.P., Apfelstedt-Sylla, E., Zrenner, E., Salati, R., Sharpe, L.T., & Kohl, S. (2001). CNGA3 mutations in hereditary cone photoreceptor disorders. American Journal of Human Genetics 69, 722–737.CrossRefGoogle Scholar
Zhong, H., Molday, L.L., Molday, R.S., & Yau, K.W. (2002). The heteromeric cyclic nucleotide-gated channel adopts a 3A:1B stoichiometry. Nature 420, 193–198.CrossRefGoogle Scholar