The Molecular Genetic and Clinical Findings in two Probands with Stargardt Disease
Authors:
B. Kousal 1,5; J. Záhlava 2; Š. Vejvalková 3; M. Hejtmánková 4; P. Lišková 1,5
Authors‘ workplace:
Oãní klinika, 1. lékafiská fakulta, Univerzita
Karlova v Praze a V‰eobecná fakultní
nemocnice v Praze, pfiednostka
doc. MUDr. Bohdana Kalvodová, CSc.
1; Oãní klinika JL, s. r. o., primáfi MUDr.
Ján Le‰ták, CSc., FEBO, MBA, LL. A
FAOG
2; Ústav biologie a lékafiské genetiky, 2.
lékafiská fakulta, Univerzita Karlova
v Praze a Fakultní nemocnice v Motole
pfiednosta prof. MUDr. Milan Macek jr.
DrSc.
3; GENNET, Praha, vedoucí MUDr.
David Stejskal
4; Laboratofi biologie a patologie oka
Ústav dûdiãn˘ch metabolick˘ch poruch
1. lékafiská fakulta, Univerzita Karlova
v Praze a V‰eobecná fakultní nemocnice
v Praze, pfiednosta prof. MUDr.
Viktor KoÏich, CSc.
5
Published in:
Čes. a slov. Oftal., 70, 2014, No. 6, p. 228-233
Category:
Original Article
Overview
Purpose:
The aim of our study was to describe the phenotype and to perform molecular genetic investigation in two probands of Czech origin diagnosed with Stargardt disease (STGD).
Methods:
Both males underwent ocular examination including assessment by high-resolution spectral domain optical coherence tomography (SD-OCT). DNA was isolated from venous blood. Mutation detection was performed using the ABCA4 genotyping microarray (Asper Ophthalmics, Estonia).
Results:
The best corrected visual acuity in proband 1 (aged 39 years) was 0.1 bilaterally, and 0.05 in proband 2 (aged 26 years). Fundus examination showed typical multiple yellow-white lesions and macular atrophy. Alterations of retinal pigment epithelium, retinal thinning and disruption of the photoreceptor inner segment ellipsoid band were detected with an SD-OCT. Two known disease-causing mutations in ABCA4 were identified in proband 1; c.4234C>T, p.(Gln1412*) in exon 28; and c.5882G>A, p.(Gly1961Glu) in exon 42. Only one pathogenic change was detected in proband 2; c.1988G>A, p.(Trp663*) in exon 14. A second change, anticipated because of the recessive status of the disease, was not identified.
Conclusion:
The frequency and full spectrum of ABCA4 mutations in Czech patients with inherited retinal disorders is yet to be established. The inability to detect a second pathogenic change in ABCA4 coding sequences in proband 2 warrants further investigation.
Key words:
Stargardt disease, ABCA4, mutation, SD-OCT
Sources
1. Aguirre-Lamban, J., Riveiro-Alvarez, R., Maia-Lopes, S., et al.: Molecular analysis of the ABCA4 gene for reliable detection of allelic variations in Spanish patients: identification of 21 novel variants. Br J Ophthalmol, 2009; 93(5): 614–21.
2. Aleman, TS., Cideciyan, AV., Windsor, EA., et al.: Macular pigment and lutein supplementation in ABCA4-associated retinal degenerations. Invest Ophthalmol Vis Sci, 2007; 48(3): 1319–29.
3. Allikmets, R.: Further evidence for an association of ABCR alleles with age-related macular degeneration. The International ABCR Screening Consortium. Am J Hum Genet, 2000; 67(2): 487–91.
4. Allikmets, R.: Simple and complex ABCR: genetic predisposition to retinal disease. Am J Hum Genet, 2000; 67(4): 793–9.
5. Allikmets, R., Shroyer, NF., Singh, N., et al.: Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science, 1997; 277(5333): 1805–7.
6. Allikmets, R., Singh, N., Sun, H., et al.: A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet, 1997; 15(3): 236–46.
7. Bellmann, C., Holz, FG., Schapp, O., et al.: Topography of fundus autofluorescence with a new confocal scanning laser ophthalmoscope. Ophthalmologe, 1997; 94(6): 385–91.
8. Braun, TA., Mullins, RF., Wagner, AH., et al.: Non-exomic and synonymous variants in ABCA4 are an important cause of Stargardt disease. Hum Mol Genet, 2013; 22(25): 5136–45.
9. Briggs, CE., Rucinski, D., Rosenfeld, PJ., et al.: Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration. Invest Ophthalmol Vis Sci, 2001; 42(10): 2229–36.
10. Burke, TR., Tsang, SH., Zernant, J., et al.: Familial discordance in Stargardt disease. Mol Vis, 2012; 18: 227–33.
11. Cella, W., Greenstein, VC., Zernant-Rajang, J., et al.: G1961E mutant allele in the Stargardt disease gene ABCA4 causes bull’s eye maculopathy. Exp Eye Res, 2009; 89(1): 16–24.
12. Cremers, FP., Van de Pol, DJ., Van Driel, M., et al.: Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt’s disease gene ABCR. Hum Mol Genet, 1998; 7(3): 355–62.
13. Downs, K., Zacks, DN., Caruso, R., et al.: Molecular testing for hereditary retinal disease as part of clinical care. Arch Ophthalmol, 2007; 125(2): 252–8.
14. Edwards, AO., Donoso, LA., Ritter, R., 3rd. A novel gene for autosomal dominant Stargardt-like macular dystrophy with homology to the SUR4 protein family. Invest Ophthalmol Vis Sci, 2001; 42(11): 2652–63.
15. Ergun, E., Hermann, B., Wirtitsch, M., et al.: Assessment of central visual function in Stargardt’s disease/fundus flavimaculatus with ultrahigh-resolution optical coherence tomography. Invest Ophthalmol Vis Sci, 2005; 46(1): 310–6.
16. Fishman, GA.: Historical evolution in the understanding of Stargardt macular dystrophy. Ophthalmic Genet, 2010; 31(4): 183–9.
17. Fishman, GA., Stone, EM., Eliason, DA., et al.: ABCA4 gene sequence variations in patients with autosomal recessive cone-rod dystrophy. Arch Ophthalmol, 2003; 121(6): 851–5.
18. Fishman, GA., Stone, EM., Grover, S., et al.: Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene. Arch Ophthalmol, 1999; 117(4): 504-10.
19. Fujinami, K., Zernant, J., Chana, RK., et al.: ABCA4 gene screening by next-generation sequencing in a British cohort. Invest Ophthalmol Vis Sci, 2013; 54(10): 6662–74.
20. Hargitai, J., Zernant, J., Somfai, GM., et al.: Correlation of clinical and genetic findings in Hungarian patients with Stargardt disease. Invest Ophthalmol Vis Sci. 2005; 46(12): 4402–8.
21. Hentze, MW., Kulozik, AE.: A perfect message: RNA surveillance and nonsense-mediated decay. Cell, 1999; 96(3): 307–10.
22. Holz, FG.: Autofluorescence imaging of the macula. Ophthalmologe, 2001; 98(1): 10-8.
23. Itabashi, R., Katsumi, O., Mehta, MC., et al.: Stargardt’s disease/fundus flavimaculatus: psychophysical and electrophysiologic results. Graefes Arch Clin Exp Ophthalmol, 1993; 231(10): 555–62.
24. Jaakson, K., Zernant, J., Kulm, M., et al.: Genotyping microarray (gene chip) for the ABCR (ABCA4) gene. Hum Mutat, 2003; 22(5): 395–403.
25. Lachapelle, P., Little, JM., and Roy, MS.: The electroretinogram in Stargardt’s disease and fundus flavimaculatus. Doc Ophthalmol, 1989; 73(4): 395–404.
26. Martinez-Mir, A., Paloma, E., Allikmets, R., et al.: Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR. Nat Genet, 1998; 18(1): 11–2.
27. Mata, NL., Weng, J., Travis, GH.: Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. Proc Natl Acad Sci U S A, 2000; 97(13): 7154–9.
28. Maugeri, A., van Driel, MA., Van de Pol, DJ., et al.: The 2588G—>C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease. Am J Hum Genet, 1999; 64(4): 1024–35.
29. Molday, RS., Zhang, K.: Defective lipid transport and biosynthesis in recessive and dominant Stargardt macular degeneration. Prog Lipid Res, 2010; 49(4): 476–92.
30. Radu, RA., Han, Y., Bui, TV., et al.: Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases. Invest Ophthalmol Vis Sci, 2005; 46(12): 4393–401.
31. Radu, RA., Yuan, Q., Hu, J., et al.: Accelerated accumulation of lipofuscin pigments in the RPE of a mouse model for ABCA4-mediated retinal dystrophies following Vitamin A supplementation. Invest Ophthalmol Vis Sci, 2008; 49(9): 3821–9.
32. Rencová, E., Studnička, J., Marák, J., et al.: Koincidence lokalizace defektů vrstvy junkce IS/OS fotoreceptorů na SD OCT s funkčními poruchami v případě Stargardtovy choroby. Čes a slov Oftal, 2012; 68(2): 84–88.
33. Rivera, A., White, K., Stohr, H., et al.: A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am J Hum Genet, 2000; 67(4): 800–13.
34. Roberts, LJ., Ramesar, RS., Greenberg, J.: Clinical utility of the ABCR400 microarray: basing a genetic service on a commercial gene chip. Arch Ophthalmol, 2009; 127(4): 549–54.
35. Rosenberg, T., Klie, F., Garred, P., et al.: N965S is a common ABCA4 variant in Stargardt-related retinopathies in the Danish population. Mol Vis, 2007; 13: 1962–9.
36. Shroyer, NF., Lewis, RA., Lupski, JR.: Complex inheritance of ABCR mutations in Stargardt disease: linkage disequilibrium, complex alleles, and pseudodominance. Hum Genet, 2000; 106(2): 244–8.
37. Schindler, EI., Nylen, EL., Ko, AC., et al.: Deducing the pathogenic contribution of recessive ABCA4 alleles in an outbred population. Hum Mol Genet. 2010; 19(19): 3693–701.
38. Simonelli, F., Testa, F., Zernant, J., et al.: Genotype-phenotype correlation in Italian families with Stargardt disease. Ophthalmic Res, 2005; 37(3): 159–67.
39. Sohrab, MA., Allikmets, R., Guarnaccia, MM., et al.: Preimplantation genetic diagnosis for stargardt disease. Am J Ophthalmol, 2010; 149(4): 651–655 e2.
40. Stanga, PE., Downes, SM., Ahuja, RM., et al.: Comparison of optical coherence tomography and fluorescein angiography in assessing macular edema in retinal dystrophies: preliminary results. Int Ophthalmol, 2001; 23(4-6): 321-5.
41. Stavrou, P., Good, PA., Misson, GP., et al.: Electrophysiological findings in Stargardt’s-fundus flavimaculatus disease. Eye (Lond), 1998; 12 ( Pt 6): 953–8.
42. Stone, EM., Webster, AR., Vandenburgh, K., et al.: Allelic variation in ABCR associated with Stargardt disease but not age-related macular degeneration. Nat Genet, 1998; 20(4): 328–9.
43. Sun, H., Nathans, J.: ABCR: rod photoreceptor-specific ABC transporter responsible for Stargardt disease. Methods Enzymol, 2000; 315: 879–97.
44. Valverde, D., Riveiro-Alvarez, R., Aguirre-Lamban, J., et al.: Spectrum of the ABCA4 gene mutations implicated in severe retinopathies in Spanish patients. Invest Ophthalmol Vis Sci, 2007; 48(3): 985–90.
45. Vasireddy, V., Wong, P., Ayyagari, R.: Genetics and molecular pathology of Stargardt-like macular degeneration. Prog Retin Eye Res, 2010; 29(3): 191–207.
46. Voigt, M., Querques, G., Atmani, K., et al.: Analysis of retinal flecks in fundus flavimaculatus using high-definition spectral-domain optical coherence tomography. Am J Ophthalmol, 2010; 150(3): 330–7.
47. Von Ruckmann, A., Fitzke, FW., Bird, AC.: In vivo fundus autofluorescence in macular dystrophies. Arch Ophthalmol, 1997; 115(5): 609–15.
48. Webster, AR., Heon, E., Lotery, AJ., et al.: An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci, 2001; 42(6): 1179–89.
49. Yang, Z., Chen, Y., Lillo, C., et al.: Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice. J Clin Invest, 2008; 118(8): 2908–16.
50. Yatsenko, AN., Shroyer, NF., Lewis, RA., et al.: Late-onset Stargardt disease is associated with missense mutations that map outside known functional regions of ABCR (ABCA4). Hum Genet, 2001; 108(4): 346–55.
51. Zernant, J., Schubert, C., Im, KM., et al.: Analysis of the ABCA4 gene by next-generation sequencing. Invest Ophthalmol Vis Sci. 2011; 52(11): 8479–87.
52. Zhang, K., Kniazeva, M., Han, M., et al.: A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet, 2001; 27(1): 89–93.
Labels
OphthalmologyArticle was published in
Czech and Slovak Ophthalmology
2014 Issue 6
Most read in this issue
- Orbital Complications of Sinusitis
- Actual State of the One Day Simultaneous Bilateral Cataract Surgery Issue
- Diagnostic Pitfalls of Pseudo-Foster Kennedy Syndrome – A Case Report
- The Molecular Genetic and Clinical Findings in two Probands with Stargardt Disease