Download fulltext
HTML
1.
Darbari E, Ahmadieh H, Rezaei Kanavi M, Suri F, Elahi E. Mutation Screening of Six Exons of ABCA4 in Iranian Stargardt Disease Patients. JOVR [Internet]. 2022Jan.21 [cited 2024Apr.19];17(1):51–58. Available from: https://knepublishing.com/index.php/JOVR/article/view/10170
https://doi.org/10.18502/jovr.v17i1.10170
statistics
- 843 Abstract Views
- 395 PDF Views
- 0 HTML Views
authors
-
Ensieh Darbari
Ensieh Darbari
School of Biology, College of Science, University of Tehran, Tehran, Iran
-
Hamid Ahmadieh
Hamid Ahmadieh
2Opthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid University of Medical Sciences, Tehran, Iran
-
Mozhgan Rezaei Kanavi
Mozhgan Rezaei Kanavi
Opthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid University of Medical Sciences, Tehran, Iran
-
Fatemeh Suri
Fatemeh Suri
Opthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid University of Medical Sciences, Tehran, Iran
-
Elahe Elahi
Elahe Elahi
School of Biology, College of Science, University of Tehran, Tehran, Iran
Published Date
- Jan 21, 2022
Mutation Screening of Six Exons of ABCA4 in Iranian Stargardt Disease Patients
Abstract
Purpose: Stargardt disease type 1 (STGD1) is a recessively inherited retinal disorder that can cause severe visual impairment. ABCA4 mutations are the usual cause of STGD1. ABCA4 codes a transporter protein exclusively expressed in retinal photoreceptor cells. The gene contains 50 exons. Mutations are most frequent in exons 3, 6, 12, and 13, and exons 10 and 42 each contain two common variations. We aimed to screen these exons for mutations in Iranian STGD1 patients.
Methods: Eighteen STGD1 patients were recruited for genetic analysis. Diagnosis by retina specialists was based on standard criteria, including accumulation of lipofuscin. The six ABCA4 exons were PCR amplified and sequenced by the Sanger method.
Results: One or more ABCA4-mutated alleles were identified in 5 of the 18 patients (27.8%). Five different mutations including two splice site (c.1356+1G>A and c.5836-2A>G) and three missense mutations (p.Gly1961Glu, p.Gly1961Arg, and p.Gly550Arg) were found. The p.Gly1961Glu mutation was the only mutation observed in two patients.
Conclusion: As ABCA4 mutations in exons 6, 12, 10, and 42 were identified in approximately 25% of the patients studied, these may be appropriate exons for screening projects. As in other populations, STDG1 causative ABCA4 mutations are heterogeneous among Iranian patients, and p.Gly1961Glu may be relatively frequent.
Keywords:
ABCA4, Mutation Screening, Retinal Dystrophy, Stargardt Disease, STGD1
References
1. Blacharski PA. Fundus flavimaculatus. In: Newsome DA, editor. Retinal dystrophies and degenerations. New York, NY: Raven Press; 1988. 135–159p.
2. Tombran-Tink J, Barnstable CJ. Retinal degenerations: biology, diagnostics, and therapeutics. Totowa, NJ: Humana Press; 2007.
3. North V, Gelman R, Tsang SH. Juvenile-onset macular degeneration and allied disorders. Dev Ophthalmol 2014;53:44–52.
4. Rivera A, White K, Stöhr H, Steiner K, Hemmrich N, Grimm T, 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;67:800–813.
5. Simonelli F, Testa F, Zernant J, Nesti A, Rossi S, Allikmets R, et al. Genotype-phenotype correlation in Italian families with Stargardt disease. Ophthalmic Res 2005;37:159–167.
6. Jiang F, Pan Z, Xu K, Tian L, Xie Y, Zhang X, et al. Screening of ABCA4 gene in a Chinese cohort with Stargardt disease or cone-rod dystrophy with a report on 85 novel mutations. Invest Ophthalmol Vis Sci 2016;57:145–152.
7. Riveiro-Alvarez R, Aguirre-Lamban J, Lopez-Martinez MA, Trujillo-Tiebas MJ, Cantalapiedra D, Vallespin E, et al. Frequency of ABCA4 mutations in 278 Spanish controls: an insight into the prevalence of autosomal recessive Stargardt disease. Br J Ophthalmol 2009;93:1359–1364.
8. Garces F, Jiang K, Molday LL, Stöhr H, Weber BH, Lyons CJ, et al. Correlating the expression and functional activity of ABCA4 disease variants with the phenotype of patients with Stargardt disease. Invest Ophthalmol Vis Sci 2018;59:2305–2315.
9. Nassisi M, Mohand-Saïd S, Dhaenens CM, Boyard F, Démontant V, Andrieu C, et al. Expanding the Mutation spectrum in ABCA4: sixty novel disease causing variants and their associated phenotype in a large French Stargardt cohort. Int J Mol Sci 2018;19:2196.
10. Salles MV, Motta FL, Martin R, Filippelli-Silva R, Dias da Silva E, Varela P, et al. Variants in the ABCA4 gene in a Brazilian population with Stargardt disease. Mol Vis 2018;24:546–559.
11. Illing M, Molday LL, Molday RS. The 220-kDa rim protein of retinal rod outer segments is a member of the ABC transporter superfamily. J Biol Chem 1997;272:10303– 10310.
12. Sun H, Nathans J. Stargardt’s ABCR is localized to the disc membrane of retinal rod outer segments. Nat Genet 1997;17:15–16.
13. Quazi F, Molday RS. ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11-cis-retinal. Proc Natl Acad Sci USA 2014;111:5024–5029.
14. Klevering BJ, Deutman AF, Maugeri A, Cremers FP, Hoyng CB. The spectrum of retinal phenotypes caused by mutations in the ABCA4 gene. Graefes Arch Clin Exp Ophthalmol 2005;243:90–100.
15. Rong WN, Wang XG, Sheng XL. [ABCA4 mutations and phenotype of different hereditary retinopathies in 3 pedigrees]. Zhonghua yan ke za zhi [Chinese J Ophthalmol] 2018;54:775–781.
16. Allikmets R, Shroyer NF, Singh N, Seddon JM, Lewis RA, Bernstein PS, et al. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science 1997;277:1805–1807.
17. Tanna P, Strauss RW, Fujinami K, Michaelides M. Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol 2017;101:25–30.
18. Briggs CE, Rucinski D, Rosenfeld PJ, Hirose T, Berson EL, Dryja TP. Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration. Invest Ophthalmol Vis Sci 2001;42:2229– 2236.
19. Ozgül RK, Durukan H, Turan A, Oner C, Ogüs A, Farber DB. Molecular analysis of the ABCA4 gene in Turkish patients with Stargardt disease and retinitis pigmentosa. Hum Mutat 2004;23:523.
20. Cideciyan AV, Swider M, Aleman TS, Tsybovsky Y, Schwartz SB, Windsor EA, et al. ABCA4 disease progression and a proposed strategy for gene therapy. Hum Mol Genet 2009;18:931–941.
21. Gerth C, Andrassi-Darida M, Bock M, Preising MN, Weber BH, Lorenz B. Phenotypes of 16 Stargardt macular dystrophy/fundus flavimaculatus patients with known ABCA4 mutations and evaluation of genotypephenotype correlation. Graefes Arch Clin Exp Ophthalmol 2002;240:628–638.
22. Guymer RH, Héon E, Lotery AJ, Munier FL, Schorderet DF, Baird PN, et al. Variation of codons 1961 and 2177 of the Stargardt disease gene is not associated with age-related macular degeneration. Arch Ophthalmol 2001;119:745–751.
23. Rodriguez-Flores JL, Fakhro K, Agosto-Perez F, Ramstetter MD, Arbiza L, Vincent TL, et al. Indigenous Arabs are descendants of the earliest split from ancient Eurasian populations. Genome Res 2016;26:151–162.
24. Fakin A, Robson AG, Fujinami K, Moore AT, Michaelides M, Pei-Wen Chiang J, et al. Phenotype and progression of retinal degeneration associated with nullizigosity of ABCA4. Invest Ophthalmol Vis Sci 2016;57:4668–4678.
25. Shroyer NF, Lewis RA, Yatsenko AN, Wensel TG, Lupski JR. Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration. Hum Mol Genet 2001;10:2671–2678.
26. Fritsche LG, Fleckenstein M, Fiebig BS, Schmitz- Valckenberg S, Bindewald-Wittich A, Keilhauer CN, et al. A subgroup of age-related macular degeneration is associated with mono-allelic sequence variants in the ABCA4 gene. Invest Ophthalmol Vis Sci 2012;53:2112– 2118.
2. Tombran-Tink J, Barnstable CJ. Retinal degenerations: biology, diagnostics, and therapeutics. Totowa, NJ: Humana Press; 2007.
3. North V, Gelman R, Tsang SH. Juvenile-onset macular degeneration and allied disorders. Dev Ophthalmol 2014;53:44–52.
4. Rivera A, White K, Stöhr H, Steiner K, Hemmrich N, Grimm T, 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;67:800–813.
5. Simonelli F, Testa F, Zernant J, Nesti A, Rossi S, Allikmets R, et al. Genotype-phenotype correlation in Italian families with Stargardt disease. Ophthalmic Res 2005;37:159–167.
6. Jiang F, Pan Z, Xu K, Tian L, Xie Y, Zhang X, et al. Screening of ABCA4 gene in a Chinese cohort with Stargardt disease or cone-rod dystrophy with a report on 85 novel mutations. Invest Ophthalmol Vis Sci 2016;57:145–152.
7. Riveiro-Alvarez R, Aguirre-Lamban J, Lopez-Martinez MA, Trujillo-Tiebas MJ, Cantalapiedra D, Vallespin E, et al. Frequency of ABCA4 mutations in 278 Spanish controls: an insight into the prevalence of autosomal recessive Stargardt disease. Br J Ophthalmol 2009;93:1359–1364.
8. Garces F, Jiang K, Molday LL, Stöhr H, Weber BH, Lyons CJ, et al. Correlating the expression and functional activity of ABCA4 disease variants with the phenotype of patients with Stargardt disease. Invest Ophthalmol Vis Sci 2018;59:2305–2315.
9. Nassisi M, Mohand-Saïd S, Dhaenens CM, Boyard F, Démontant V, Andrieu C, et al. Expanding the Mutation spectrum in ABCA4: sixty novel disease causing variants and their associated phenotype in a large French Stargardt cohort. Int J Mol Sci 2018;19:2196.
10. Salles MV, Motta FL, Martin R, Filippelli-Silva R, Dias da Silva E, Varela P, et al. Variants in the ABCA4 gene in a Brazilian population with Stargardt disease. Mol Vis 2018;24:546–559.
11. Illing M, Molday LL, Molday RS. The 220-kDa rim protein of retinal rod outer segments is a member of the ABC transporter superfamily. J Biol Chem 1997;272:10303– 10310.
12. Sun H, Nathans J. Stargardt’s ABCR is localized to the disc membrane of retinal rod outer segments. Nat Genet 1997;17:15–16.
13. Quazi F, Molday RS. ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11-cis-retinal. Proc Natl Acad Sci USA 2014;111:5024–5029.
14. Klevering BJ, Deutman AF, Maugeri A, Cremers FP, Hoyng CB. The spectrum of retinal phenotypes caused by mutations in the ABCA4 gene. Graefes Arch Clin Exp Ophthalmol 2005;243:90–100.
15. Rong WN, Wang XG, Sheng XL. [ABCA4 mutations and phenotype of different hereditary retinopathies in 3 pedigrees]. Zhonghua yan ke za zhi [Chinese J Ophthalmol] 2018;54:775–781.
16. Allikmets R, Shroyer NF, Singh N, Seddon JM, Lewis RA, Bernstein PS, et al. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science 1997;277:1805–1807.
17. Tanna P, Strauss RW, Fujinami K, Michaelides M. Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol 2017;101:25–30.
18. Briggs CE, Rucinski D, Rosenfeld PJ, Hirose T, Berson EL, Dryja TP. Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration. Invest Ophthalmol Vis Sci 2001;42:2229– 2236.
19. Ozgül RK, Durukan H, Turan A, Oner C, Ogüs A, Farber DB. Molecular analysis of the ABCA4 gene in Turkish patients with Stargardt disease and retinitis pigmentosa. Hum Mutat 2004;23:523.
20. Cideciyan AV, Swider M, Aleman TS, Tsybovsky Y, Schwartz SB, Windsor EA, et al. ABCA4 disease progression and a proposed strategy for gene therapy. Hum Mol Genet 2009;18:931–941.
21. Gerth C, Andrassi-Darida M, Bock M, Preising MN, Weber BH, Lorenz B. Phenotypes of 16 Stargardt macular dystrophy/fundus flavimaculatus patients with known ABCA4 mutations and evaluation of genotypephenotype correlation. Graefes Arch Clin Exp Ophthalmol 2002;240:628–638.
22. Guymer RH, Héon E, Lotery AJ, Munier FL, Schorderet DF, Baird PN, et al. Variation of codons 1961 and 2177 of the Stargardt disease gene is not associated with age-related macular degeneration. Arch Ophthalmol 2001;119:745–751.
23. Rodriguez-Flores JL, Fakhro K, Agosto-Perez F, Ramstetter MD, Arbiza L, Vincent TL, et al. Indigenous Arabs are descendants of the earliest split from ancient Eurasian populations. Genome Res 2016;26:151–162.
24. Fakin A, Robson AG, Fujinami K, Moore AT, Michaelides M, Pei-Wen Chiang J, et al. Phenotype and progression of retinal degeneration associated with nullizigosity of ABCA4. Invest Ophthalmol Vis Sci 2016;57:4668–4678.
25. Shroyer NF, Lewis RA, Yatsenko AN, Wensel TG, Lupski JR. Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration. Hum Mol Genet 2001;10:2671–2678.
26. Fritsche LG, Fleckenstein M, Fiebig BS, Schmitz- Valckenberg S, Bindewald-Wittich A, Keilhauer CN, et al. A subgroup of age-related macular degeneration is associated with mono-allelic sequence variants in the ABCA4 gene. Invest Ophthalmol Vis Sci 2012;53:2112– 2118.