SPECTRUM OF MOLECULAR GENETIC ALTERATIONS AND DIVERSITY OF CLINICAL FORMS OF STARGARDT DISEASE

Purpose of the study was to assess the spectrum of molecular genetic disorders and the variety of clinical forms in patients with Stargardt disease. Material and methods. 56 patients aged 15-44 years who had been diagnosed with Stargardt disease in a history or at the time of the examination were included in the study. All patients underwent standard complete ophthalmic examination, as well as high-performance parallel sequencing of the coding sequences and adjacent areas of the introns of the ABCA4, ELOVL4, PROM1 and CNGB3 genes, as well as of the minor exons of the ABCA4 gene. Results. Mutations in one of 4 genes ( ABCA4, ELOVL4, PROM1 and CNGB3 ) were detected in 46 of 56 patients (82.1 %). An inverse correlation was found between the duration of the disease and the loss of visual acuity per year for the three groups ( k = -0.86, k = -0.93, k = -0.63, p < 0.05, respectively, with the debut of the Stargardt disease at 10 year, 11-30 year and > 31 year). A frequent mutation of the ABCA4 gene, p.G1961E was detected in 18 patients and in 83 % of cases (15 patients) is associated with a mild course of Stargardt disease. Complex mutation [p.L541P, p.A1038V] was detected in 17 patients, in 53 % (9 people) of cases was associated with more severe phenotype. However, in the compound heterozygous state with the missense mutation p.G1961E, a relatively mild course of the disease was observed. Conclusions. The loss of visual functions in Stargardt disease depends on the severity of the genetic defect in each case and on the disease’s duration in general.

ABCA4, ELOVL4, PROM1, CNGB3, Stargardt disease, cone-rod dystrophy, mutation, high-performance parallel sequencing, ABCA4, ELOVL4, PROM1, CNGB3

1. Карандашева К.О., Жоржоладзе Н.В., Шеремет Н.Л., Кузнецова Е.Б., Танас А.С., Аношкин К.И., Залетаев Д.В., Стрельников В.В. Мутации криптических сайтов сплайсинга в некодирующих областях гена ABCA4 при болезни Штаргардта // Мед. генетика. 2016. 15. (6). 31-36.

2. Шеремет Н.Л., Жоржоладзе Н.В., Ронзина И.А., Грушкэ И.Г., Курбатов С.А., Чухрова А.Л., Логинова А.Н., Щербакова П.О., Танас А.С., Поляков А.В., Стрельников В.В. Молекулярно-генетическая диагностика болезни Штаргардта // Вестн. офтальмологии. 2017. 133. (4). 4-11.

3. Шеремет Н.Л., Ронзина И.А., Жоржоладзе Н.В., Стрельников В.В. Взаимосвязь структурных и функциональных изменений сетчатки при болезни Штаргардта // Вестн. офтальмологии. 2016. 132. (3). 42-48.

4. Battu R., Verma A., Hariharan R., Krishna S., Kiran R., Jacob J., Ganapathy A., Ramprasad V.L., Kumaramanickavel G., Jeyabalan N., Ghosh A. Identification of novel mutations in ABCA4 gene: Clinical and genetic analysis of Indian patients with Stargardt disease // Biomed. Res. Int. 2015. 2015. 940864.

5. Cornelis S.S., Bax N.M., Zernant J., Allikmets R., Fritsche L.G., den Dunnen J.T., Ajmal M., Hoyng C.B., Cremers F.P. In silico functional meta-analysis of 5,962 ABCA4 variants in 3,928 retinal dystrophy cases // Hum. Mutat. 2017. 38. (4). 400-408.

6. Fakin A., Robson A.G., Fujinami K., Moore A.T., Michaelides M., Pei-Wen Chiang J., Holder G., Webster A.R. Phenotype and progression of retinal degeneration associated with nullizigosity of ABCA4 // Invest. Ophthalmol. Vis. Sci. 2016. 57. (11). 4668-4678.

7. Gemenetzi M., Lotery A.J. Phenotype/genotype correlation in a case series of Stargardt’s patients identifies novel mutations in the ABCA4 gene // Eye (Lond). 2013. 27. (11). 1316-1369.

8. Imani S., Cheng J., Shasaltaneh M.D., Wei C., Yang L., Fu S., Zou H., Khan M.A., Zhang X., Chen H., Zhang D., Duan C., Lv H., Li Y., Chen R., Fu J. Genetic identification and molecular modeling characterization reveal a novel PROM1 mutation in Stargardt4-like macular dystrophy // Oncotarget. 2018. 9. (1). 122-141.

9. Maia-Lopes S., Aguirre-Lamban J., Castelo-Branco M., Riveiro-Alvarez R., Ayuso C., Silva E.D. ABCA4 mutations in Portuguese Stargardt patients: identification of new mutations and their phenotypic analysis // Mol. Vis. 2009. 15. 584-591.

10. Michaelides M., Gaillard M.C., Escher P., Tiab L., Bedell M., Borruat F.X., Barthelmes D., Carmona R., Zhang K., White E., Mc. Clements M., Robson A.G., Holder G.E., Bradshaw K., Hunt D.M., Webster A.R., Moore A.T., Schorderet D.F., Munier F.L. The PROM1 mutation p.R373C causes an autosomal dominant bull’s eye maculopathy associated with rod, rod-cone, and macular dystrophy // Invest. Ophthalmol. Vis. Sci. 2010. 51. (9). 4771-4780.

11. Permanyer J., Navarro R., Friedman J., Pomares E., Castro-Navarro J., Marfany G., Swaroop A., Gonzàlez-Duarte R. Autosomal recessive retinitis pigmentosa with early macular affectation caused by premature truncation in PROM1 // Invest. Ophthalmol. Vis. Sci. 2010. 51. (5). 2656-2663.

12. Robinson J.T., Thorvaldsdóttir H., Winckler W., Guttman M., Lander E.S., Getz G., Mesirov J.P. Integrative genomics viewer // Nat. Biotechnol. 2011. 29. (1). 24-26.

13. Sangermano R., Khan M., Cornelis S.S., Richelle V., Albert S., Garanto A., Elmelik D., Qamar R., Lugtenberg D., van den Born L.I., Collin R.W.J., Cremers F.P.M. ABCA4 midigenes reveal the full splice spectrum of all reported noncanonical splice site variants in Stargardt disease // Genome Res. 2018. 28. (1). 100-110.

14. Tanna P., Strauss R.W., Fujinami K., Michaelides M. Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options // Br. J. Ophthalmol. 2017. 101. (1). 25-30.

15. Van Driel M.A., Maugeri A., Klevering B.J., Hoyng C.B., Cremers F.P. ABCR unites what ophthalmologists divide(s) // Ophthalmic. Genet. 1998. 19. (3). 117-122.

16. Wang K., Li M., Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data // Nucleic Acids Res. 2010. 38. (16). e164.

17. Westeneng-van Haaften S.C., Boon C.J., Cremers F.P., Hoefsloot L.H., den Hollander A.I., Hoyng C.B. Clinical and genetic characteristics of late-onset Stargardt’s disease // Ophthalmology. 2012. 119. (6). 1199-1210.

18. Xi Q., Li L., Traboulsi E.I., Wang Q.K. Novel ABCA4 compound heterozygous mutations cause severe progressive autosomal recessive cone-rod dystrophy presenting as Stargardt disease // Mol. Vis. 2009. 15. 638-645.