Home > Archive>Volume 8, Issue 5, 2015 >910-915. DOI:10.3980/j.issn.2222-3959.2015.05.10
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Achromatopsia caused by novel missense mutations in the CNGA3 gene
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1Tianjin Medical University Eye Hospital, Eye Institute & School of Optometry and Ophthalmology, Tianjin 300384, China;
2BGI Health Service Co., Ltd. Airport Industrial Zone, Tianjin 300308, China

Fund Project:

Supported by the National Natural Science Foundation of China (No.81371005; No.31100991).

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    Abstract:

    AIM:To identify the genetic defects in a Chinese family with achromatopsia.METHODS:A 2.5-year-old boy, who displayed nystagmus, photophobia, and hyperopia since early infancy, was clinically evaluated. To further confirm and localize the causative mutations in this family, targeted region capture and next-generation sequencing of candidate genes, such as CNGA3, CNGB3, GNAT2, PDE6C, and PDE6H were performed using a custom-made capture array.RESULTS:Slit-lamp examination showed no specific findings in the anterior segments. The optic discs and maculae were normal on fundoscopy. The unaffected family members reported no ocular complaints. Clinical signs and symptoms were consistent with a clinical impression of autosomal recessive achromatopsia. The results of sequence analysis revealed two novel missense mutations in CNGA3, c.633T>A (p.D211E) and c.1006G>T (p.V336F), with an autosomal recessive mode of inheritance.CONCLUSION: Genetic analysis of a Chinese family confirmed the clinical diagnosis of achromatopsia. Two novel mutations were identified in CNGA3, which extended the mutation spectrum of this disorder.

    Reference
    1 Sharpe LT, Stockman A, Jagle H, Nathans J. Opsin genes, cone photopigments, color vision, and colour blindness. In:Gegenfurtner K, Sharpe LT, eds. Color Vision From Genes to Perception. Cambridge, UK:Cambridge University Press. 1999;3-52
    2 Genead MA, Fishman GA, Rha J, Dubis AM, Bonci DM, Dubra A, Stone EM, Neitz M, Carroll J. Photoreceptor structure and function in patients with congenital achromatopsia. Invest Ophthalmol Vis Sci 2011;52(10):7298-7308
    3 Khan NW, Wissinger B, Kohl S, Sieving PA. CNGB3 achromatopsia with progressive loss of residual cone function and impaired rod-mediated function. Invest Ophthalmol Vis Sci 2007;48(8):3864-3871
    4 Thiadens AA, Somervuo V, van den Born LI, Roosing S, van Schooneveld MJ, Kuijpers RW, van Moll-Ramirez N, Cremers FP, Hoyng CB, Klaver CC. Progressive loss of cones in achromatopsia:an imaging study using spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci 2010;51(11):5952-5957
    5 Azam M, Collin RW, Shah ST, Shah AA, Khan MI, Hussain A, Sadeque A, Strom TM, Thiadens AA, Roosing S, den Hollander AI, Cremers FP, Qamar R. Novel CNGA3 and CNGB3 mutations in two Pakistani families with achromatopsia. Mol Vis 2010;16:774-781
    6 Kohl S, Marx T, Giddings I, Jagle H, Jacobson SG, Apfelstedt-Sylla E, Zrenner E, Sharpe LT, Wissinger B. Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nat Genet 1998;19(3):257-259
    7 Kohl S, Baumann B, Broghammer M, Jagle H, Sieving P, Kellner U, Spegal R, Anastasi M, Zrenner E, Sharpe LT, Wissinger B. 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. Hum Mol Genet 2000;9(14):2107-2116
    8 Sundin OH, Yang JM, Li Y, Zhu D, Hurd JN, Mitchell TN, Silva ED, Maumenee IH. Genetic basis of total colourblindness among the Pingelapese islanders. Nat Genet 2000;25(3):289-293
    9 Kohl S, Baumann B, Rosenberg T, Kellner U, Lorenz B, Vadala M, Jacobson SG, Wissinger B. Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia. Am J Hum Genet 2002;71(2):422-425
    10 Ouechtati F, Merdassi A, Bouyacoub Y, Largueche L, Derouiche K, Ouragini H, Nouira S, Tiab L, Baklouti K, Rebai A, Schorderet DF, Munier FL, Zografos L, Abdelhak S, El Matri L. Clinical and genetic investigation of a large Tunisian family with complete achromatopsia:identification of a new nonsense mutation in GNAT2 gene. J Hum Genet 2011;56(1):22-28
    11 Chang B, Grau T, Dangel S, Hurd R, Jurklies B, Sener EC, Andreasson S, Dollfus H, Baumann B, Bolz S, Artemyev N, Kohl S, Heckenlively J, Wissinger B. A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene. Proc Natl Acad Sci U S A 2009;106(46):19581-19586
    12 Thiadens AA, den Hollander AI, Roosing S, Nabuurs SB, Zekveld-Vroon RC, Collin RW, De Baere E, Koenekoop RK, van Schooneveld MJ, Strom TM, van Lith-Verhoeven JJ, Lotery AJ, van Moll-Ramirez N, Leroy BP, van den Born LI, Hoyng CB, Cremers FP, Klaver CC. Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders. Am J Hum Genet 2009;85(2):240-247
    13 Kohl S, Coppieters F, Meire F, Schaich S, Roosing S, Brennenstuhl C, Bolz S, van Genderen MM, Riemslag FC; European Retinal Disease Consortium, Lukowski R, den Hollander AI, Cremers FP, De Baere E, Hoyng CB, Wissinger B. A nonsense mutation in PDE6H causes autosomal-recessive incomplete achromatopsia. Am J Hum Genet 2012;91(3):527-532
    14 Kohl S, Varsanyi B, Antunes GA, Baumann B, Hoyng CB, Jagle H, Rosenberg T, Kellner U, Lorenz B, Salati R, Jurklies B, Farkas A, Andreasson S, Weleber RG, Jacobson SG, Rudolph G, Castellan C, Dollfus H, Legius E, Anastasi M, Bitoun P, Lev D, Sieving PA, Munier FL, Zrenner E, Sharpe LT, Cremers FP, Wissinger B. CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia. Eur J Hum Genet 2005;13(3):302-308
    15 Wissinger B, Gamer D, Jagle H, Giorda R, Marx T, Mayer S, Tippmann S, Broghammer M, Jurklies B, Rosenberg T, Jacobson SG, Sener EC, Tatlipinar S, Hoyng CB, Castellan C, Bitoun P, Andreasson S, Rudolph G, Kellner U, Lorenz B, Wolff G, Verellen-Dumoulin C, Schwartz M, Cremers FP, Apfelstedt-Sylla E, Zrenner E, Salati R, Sharpe LT, Kohl S. CNGA3 mutations in hereditary cone photoreceptor disorders. Am J Hum Genet 2001;69(4):722-737
    16 Grau T, Artemyev NO, Rosenberg T, Dollfus H, Haugen OH, Cumhur Sener E, Jurklies B, Andreasson S, Kernstock C, Larsen M, Zrenner E, Wissinger B, Kohl S. Decreased catalytic activity and altered activation properties of PDE6C mutants associated with autosomal recessive achromatopsia. Hum Mol Genet 2011;20(4):719-730
    17 Shuart NG, Haitin Y, Camp SS, Black KD, Zagotta WN. Molecular mechanism for 3:1 subunit stoichiometry of rod cyclic nucleotide-gated ion channels. Nat Commun 2011;2:457
    18 Ding XQ, Matveev A, Singh A, Komori N, Matsumoto H. Biochemical characterization of cone cyclic nucleotide-gated (CNG) channel using the infrared fluorescence detection system. Adv Exp Med Biol 2012;723:769-775
    19 Zagotta WN, Siegelbaum SA. Structure and function of cyclic nucleotide-gated channels. Annu Rev Neurosci 1996;19:235-263
    20 Matveev AV, Quiambao AB, Browning Fitzgerald J, Ding XQ. Native cone photoreceptor cyclic nucleotide-gated channel is a heterotetrameric complex comprising both CNGA3 and CNGB3:a study using the cone-dominant retina of Nrl-/- mice. J Neurochem 2008;106(5):2042-2055
    21 Nishiguchi KM, Sandberg MA, Gorji N, Berson EL, Dryja TP. Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases. Hum Mutat 2005;25(3):248-258
    22 Johnson S, Michaelides M, Aligianis IA, Ainsworth JR, Mollon JD, Maher ER, Moore AT, Hunt DM. Achromatopsia caused by novel mutations in both CNGA3 and CNGB3. J Med Genet 2004;41(2):e20
    23 Goto-Omoto S, Hayashi T, Gekka T, Kubo A, Takeuchi T, Kitahara K. Compound heterozygous CNGA3 mutations (R436W, L633P) in a Japanese patient with congenital achromatopsia. Vis Neurosci 2006;23(3-4):395-402
    24 Wiszniewski W, Lewis RA, Lupski JR. Achromatopsia:the CNGB3 p.T383fsX mutation results from a founder effect and is responsible for the visual phenotype in the original report of uniparental disomy 14. Hum Genet 2007;121(3-4):433-439
    25 Koeppen K, Reuter P, Kohl S, Baumann B, Ladewig T, Wissinger B. Functional analysis of human CNGA3 mutations associated with colour blindness suggests impaired surface expression of channel mutants A3(R427C) and A3(R563C). Eur J Neurosci 2008;27(9):2391-2401
    26 Reuter P, Koeppen K, Ladewig T, Kohl S, Baumann B, Wissinger B; Achromatopsia Clinical Study Group. Mutations in CNGA3 impair trafficking or function of cone cyclic nucleotide-gated channels, resulting in achromatopsia. Hum Mutat 2008;29(10):1228-1236
    27 Ahuja Y, Kohl S, Traboulsi EI. CNGA3 mutations in two United Arab Emirates families with achromatopsia. Mol Vis 2008;14:1293-1297
    28 Koeppen K, Reuter P, Ladewig T, Kohl S, Baumann B, Jacobson SG, Plomp AS, Hamel CP, Janecke AR, Wissinger B. Dissecting the pathogenic mechanisms of mutations in the pore region of the human cone photoreceptor cyclic nucleotide-gated channel. Hum Mutat 2010;31(7):830-839
    29 Saqib MA, Awan BM, Sarfraz M, Khan MN, Rashid S, Ansar M. Genetic analysis of four Pakistani families with achromatopsia and a novel S4 motif mutation of CNGA3. Jpn J Ophthalmol 2011;55(6):676-680
    30 Lam K, Guo H, Wilson GA, Kohl S, Wong F. Identification of variants in CNGA3 as cause for achromatopsia by exome sequencing of a single patient. Arch Ophthalmol 2011;129(9):1212-1217
    31 Sundaram V, Wilde C, Aboshiha J, Cowing J, Han C, Langlo CS, Chana R, Davidson AE, Sergouniotis PI, Bainbridge JW, Ali RR, Dubra A, Rubin G, Webster AR, Moore AT, Nardini M, Carroll J, Michaelides M. Retinal structure and function in achromatopsia:implications for gene therapy. Ophthalmology 2014;121(1):234-245
    32 Li S, Huang L, Xiao X, Jia X, Guo X, Zhang Q. Identification of CNGA3 mutations in 46 families:common cause of achromatopsia and cone-rod dystrophies in chinese patients. JAMA Ophthalmol 2014;132(9):1076-1083
    33 Tanaka N, Delemotte L, Klein ML, Komaromy AM, Tanaka JC. A cyclic nucleotide-gated channel mutation associated with canine daylight blindness provides insight into a role for the S2 segment tri-Asp motif in channel biogenesis. PLoS One 2014;9(2):e88768
    34 Park WL, Sunness JS. Red contact lenses for alleviation of photophobia in patients with cone disorders. Am J Ophthalmol 2004;137(4):774-775
    35 Schon C, Biel M, Michalakis S. Gene replacement therapy for retinal CNG channelopathies. Mol Genet Genomics 2013;288(10):459-467
    36 Michalakis S, Muhlfriedel R, Tanimoto N, Krishnamoorthy V, Koch S, Fischer MD, Becirovic E, Bai L, Huber G, Beck SC, Fahl E, Buning H, Schmidt J, Zong X, Gollisch T, Biel M, Seeliger MW. Gene therapy restores missing cone-mediated vision in the CNGA3-/- mouse model of achromatopsia. Adv Exp Med Biol 2012;723:183-189
    37 Michalakis S, Muhlfriedel R, Tanimoto N, Krishnamoorthy V, Koch S, Fischer MD, Becirovic E, Bai L, Huber G, Beck SC, Fahl E, Buning H, Paquet-Durand F, Zong X, Gollisch T, Biel M, Seeliger MW. Restoration of cone vision in the CNGA3-/- mouse model of congenital complete lack of cone photoreceptor function. Mol Ther 2010;18(12):2057-2063
    38 Pang JJ, Alexander J, Lei B, Deng W, Zhang K, Li Q, Chang B, Hauswirth WW. Achromatopsia as a potential candidate for gene therapy. Adv Exp Med Biol 2010;664:639-646
    39 Pang JJ, Deng WT, Dai X, Lei B, Everhart D, Umino Y, Li J, Zhang K, Mao S, Boye SL, Liu L, Chiodo VA, Liu X, Shi W, Tao Y, Chang B, Hauswirth WW. AAV-mediated cone rescue in a naturally occurring mouse model of CNGA3-achromatopsia. PLoS One 2012;7(4):e35250
    40 Komaromy AM, Rowlan JS, Corr AT, Reinstein SL, Boye SL, Cooper AE, Gonzalez A, Levy B, Wen R, Hauswirth WW, Beltran WA, Aguirre GD. Transient photoreceptor deconstruction by CNTF enhances rAAV-mediated cone functional rescue in late stage CNGB3-achromatopsia. Mol Ther 2013;21(6):1131-1141
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Xi-Teng Chen, Hui Huang, Yan-Hua Chen,/et al.Achromatopsia caused by novel missense mutations in the CNGA3 gene. Int J Ophthalmol, 2015,8(5):910-915

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Publication History
  • Received:January 27,2015
  • Revised:March 14,2015
  • Adopted:March 14,2015
  • Online: October 09,2015
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