Analysis of BEST1 gene mutations and clinical features in multifocal vitelliform retinopathy patients_Chinese Journal of Ocular Fundus Diseases

Authors：

Luo Jingyi , Xiao Hui , Xu Xiaoyu , Fang Lei , Wei Wei , Zhong Yimin ,  Liu Xing

State Key Laboratory of Ophthalmology (Zhongshan Ophthalmic Center, Sun Yat-sen University), Guangzhou 510060, China;

Corresponding author：

Liu Xing, Email: liuxing@mail.sysu.edu.cn

Keywords：

Retinal diseases/genetics; Retinal diseases/etiology; Genes; Mutation; Clinical characteristics

DOI：

10.3760/cma.j.issn.1005-1015.2018.02.010

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Objective To analyze the BEST1 gene mutations and clinical features in patients with multifocal vitelliform retinopathy (MVR). Methods This is a retrospective case series study. Five MVR families with MVR, including 9 patients and 10 healthy family members were recruited. Clinical evaluations were performed in all MVR patients and their family members, including best-corrected visual acuity (BCVA), intraocular pressure (IOP), refraction, slit-lamp examination, 90 D preset lens examination, gonioscopy, color fundus photography, optical coherence tomography (OCT), fundus autofluorescence (AF), ultrasound biomicroscopy (UBM) and axial length measurement. Electro-oculogram (EOG) was performed in 12 eyes and visual field were performed in 13 eyes. Peripheral blood samples were collected in all subjects to extract genomic DNA. Coding exons and flanking intronic regions of BEST1 were amplified by polymerase chain reaction and analyzed by Sanger sequencing. Results Among the 5 MVR families, 3 probands from three families had family history, including 1 family had autosomal dominant inheritance pattern. Two patients from 2 families were sporadic cases. Screening of BEST1 gene identified four mutations, including three missense mutations (c.140G>T, p.R47L; c.232A>T, p.I78F; c.698C>T, p.P233L) and 1 deletion mutation (c.910_912del, p.D304del). Two mutations (p.R47L and p.I78F) were novel. The BCVA of affected eyes ranged from hand motion to 1.0. The mean IOP was (30.39±11.86) mmHg (1 mmHg=0.133 kPa). The mean refractive diopter was (-0.33±1.68) D. Twelve eyes had angle-closure glaucoma (ACG) and 4 eyes had angle closure (AC). EOG Arden ratio was below 1.55 in all patients. The mean anterior chamber depth was (2.17±0.29) mm. Visual field showed defects varied from paracentral scotoma to diffuse defects. The mean axial length was (21.87±0.63) mm. All MVR patients had multifocal vitelliform lesions in the posterior poles of retina. ACG eyes demonstrated pale optic disc with increased cup-to-disc ratio. OCT showed retinal edema, extensive serous retinal detachment and subretinal hyper-reflective deposits which had high autofluorescence in AF. The genetic testing and clinical examination were normal in 10 family members. Conclusions MVR patients harbored heterozygous mutation in the BEST1 gene. Two novel mutations (p.R47L and p.I78F) were identified. These patients had clinical features of multifocal vitelliform retinopathy and abnormal EOG. Most patients suffered from AC/ACG.

Citation： Luo Jingyi, Xiao Hui, Xu Xiaoyu, Fang Lei, Wei Wei, Zhong Yimin, Liu Xing. Analysis of BEST1 gene mutations and clinical features in multifocal vitelliform retinopathy patients. Chinese Journal of Ocular Fundus Diseases, 2018, 34(2): 149-154. doi: 10.3760/cma.j.issn.1005-1015.2018.02.010 Copy

1.	Miller SA. Multifocal Best's vitelliform dystrophy[J]. Arch Ophthalmol, 1977, 95(6): 984-990.
2.	Hittner HM, Ferrell RE, Borda RP, et al. Atypical vitelliform macular dystrophy in a 5-generation family[J]. Br J Ophthalmol, 1984, 68(3): 199-207.
3.	Wittstrom E, Ekvall S, Schatz P, et al. Morphological and functional changes in multifocal vitelliform retinopathy and biallelic mutations in BEST1[J]. Ophthalmic Genet, 2011, 32(2): 83-96.DOI: 10.3109/13816810.2010.535890.
4.	Boon CJ, Klevering BJ, den Hollander AI, et al. Clinical and genetic heterogeneity in multifocal vitelliform dystrophy[J]. Arch Ophthalmol, 2007, 125(8): 1100-1106.DOI: 10.1001/archopht.125.8.1100.
5.	Lacassagne E, Dhuez A, Rigaudiere F, et al. Phenotypic variability in a French family with a novel mutation in the BEST1 gene causing multifocal best vitelliform macular dystrophy[J]. Mol Vis, 2011, 17: 309-322.
6.	刘志强, 杨荣, 闫素霞, 等.成年人多灶性卵黄样病变一例[J]. 中国实用眼科杂志, 2010, 28(8): 930.DOI: 10.3760/cma.j.issn.1006-4443.2010.08.042.Liu ZQ, Yang R, Yan SX, et al. Adult-onset multifocal vitelliform dystrophy: a case report [J].Chin J Pract Ophthalmo, 2010, 28(8): 930.DOI: 10.3760/cma.j.issn.1006-4443.2010.08.042.
7.	Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424.DOI: 10.1038/gim.2015.30.
8.	Hartzell HC, Qu Z, Yu K, et al. Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies[J]. Physiol Rev, 2008, 88(2): 639-672. DOI: 10.1152/physrev.00022.2007.
9.	Boon CJ, Klevering BJ, Leroy BP, et al. The spectrum of ocular phenotypes caused by mutations in the BEST1 gene[J]. Prog Retin Eye Res, 2009, 28(3): 187-205.DOI: 10.1016/j.preteyeres.2009.04.002.
10.	Caldwell GM, Kakuk LE, Griesinger IB, et al. Bestrophin gene mutations in patients with Best vitelliform macular dystrophy[J]. Genomics, 1999, 58(1): 98-101. DOI: 10.1006/geno.1999.5808.
11.	Wong RL, Hou P, Choy KW, et al. Novel and homozygous BEST1 mutations in Chinese patients with Best vitelliform macular dystrophy[J]. Retina, 2010, 30(5): 820-827. DOI: 10.1097/IAE.0b013e3181c700c1.
12.	Querques G, Zerbib J, Santacroce R, et al. The spectrum of subclinical Best vitelliform macular dystrophy in subjects with mutations in BEST1 gene[J]. Invest Ophthalmol Vis Sci, 2011, 52(7): 4678-4684. DOI: 10.1167/iovs.10-6500.
13.	Mullins RF, Oh KT, Heffron E, et al. Late development of vitelliform lesions and flecks in a patient with best disease: clinicopathologic correlation[J]. Arch Ophthalmol, 2005, 123(11): 1588-1594.DOI: 10.1001/archopht.123.11.1588.
14.	Kramer F, White K, Pauleikhoff D, et al. Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration[J]. Eur J Hum Genet, 2000, 8(4): 286-292. DOI: 10.1038/sj.ejhg.5200447.
15.	Kinnick TR, Mullins RF, Dev S, et al. Autosomal recessive vitelliform macular dystrophy in a large cohort of vitelliform macular dystrophy patients[J]. Retina, 2011, 31(3): 581-595. DOI: 10.1097/IAE.0b013e318203ee60.
16.	Huang X, Xiao X, Jia X, et al. Mutation analysis of the genes associated with anterior segment dysgenesis, microcornea and microphthalmia in 257 patients with glaucoma[J]. Int J Mol Med, 2015, 36(4): 1111-1117. DOI: 10.3892/ijmm.2015.2325.
17.	Lin Y, Gao H, Liu Y, et al. Two novel mutations in the bestrophin-1 gene and associated clinical observations in patients with best vitelliform macular dystrophy[J]. Mol Med Rep, 2015, 12(2): 2584-2588. DOI: 10.3892/mmr.2015.3711.
18.	Blodi CF, Stone EM. Best's vitelliform dystrophy[J]. Ophthalmic Paediatr Genet, 1990, 11(1): 49-59.
19.	Esfahani MR, Esfahani HR, Mahmoudi A, et al. Focal choroidal excavation in Best vitelliform macular dystrophy: case report[J]. J Clin Diagn Res, 2015, 9(5): 1-2.DOI: 10.7860/JCDR/2015/12861.5993.
20.	Liu J, Zhang Y, Xuan Y, et al. Novel BEST1 mutations and special clinical features of Best vitelliform macular dystrophy[J]. Ophthalmic Res, 2016, 56(4): 178-185. DOI: 10.1159/000444681.
21.	Rosenthal R, Heimann H, Agostini H, et al. Ca²⁺ channels in retinal pigment epithelial cells regulate vascular endothelial growth factor secretion rates in health and disease[J]. Mol Vis, 2007, 13: 443-456.
22.	Quigley HA, Friedman DS, Congdon NG. Possible mechanisms of primary angle-closure and malignant glaucoma[J]. J Glaucoma, 2003, 12(2): 167-180.
23.	Zhong Y, Guo X, Xiao H, et al. Flat anterior chamber after trabeculectomy in secondary angle-closure glaucoma with BEST1 gene mutation: case series[J/OL]. PLoS One, 2017, 12(1): 0169395[2017-01-05].https://doi.org/10.1371/journal.pone.0169395. DOI: 10.1371/journal.pone.0169395.

1. Miller SA. Multifocal Best's vitelliform dystrophy[J]. Arch Ophthalmol, 1977, 95(6): 984-990.
2. Hittner HM, Ferrell RE, Borda RP, et al. Atypical vitelliform macular dystrophy in a 5-generation family[J]. Br J Ophthalmol, 1984, 68(3): 199-207.
3. Wittstrom E, Ekvall S, Schatz P, et al. Morphological and functional changes in multifocal vitelliform retinopathy and biallelic mutations in BEST1[J]. Ophthalmic Genet, 2011, 32(2): 83-96.DOI: 10.3109/13816810.2010.535890.
4. Boon CJ, Klevering BJ, den Hollander AI, et al. Clinical and genetic heterogeneity in multifocal vitelliform dystrophy[J]. Arch Ophthalmol, 2007, 125(8): 1100-1106.DOI: 10.1001/archopht.125.8.1100.
5. Lacassagne E, Dhuez A, Rigaudiere F, et al. Phenotypic variability in a French family with a novel mutation in the BEST1 gene causing multifocal best vitelliform macular dystrophy[J]. Mol Vis, 2011, 17: 309-322.
6. 刘志强, 杨荣, 闫素霞, 等.成年人多灶性卵黄样病变一例[J]. 中国实用眼科杂志, 2010, 28(8): 930.DOI: 10.3760/cma.j.issn.1006-4443.2010.08.042.Liu ZQ, Yang R, Yan SX, et al. Adult-onset multifocal vitelliform dystrophy: a case report [J].Chin J Pract Ophthalmo, 2010, 28(8): 930.DOI: 10.3760/cma.j.issn.1006-4443.2010.08.042.
7. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424.DOI: 10.1038/gim.2015.30.
8. Hartzell HC, Qu Z, Yu K, et al. Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies[J]. Physiol Rev, 2008, 88(2): 639-672. DOI: 10.1152/physrev.00022.2007.
9. Boon CJ, Klevering BJ, Leroy BP, et al. The spectrum of ocular phenotypes caused by mutations in the BEST1 gene[J]. Prog Retin Eye Res, 2009, 28(3): 187-205.DOI: 10.1016/j.preteyeres.2009.04.002.
10. Caldwell GM, Kakuk LE, Griesinger IB, et al. Bestrophin gene mutations in patients with Best vitelliform macular dystrophy[J]. Genomics, 1999, 58(1): 98-101. DOI: 10.1006/geno.1999.5808.
11. Wong RL, Hou P, Choy KW, et al. Novel and homozygous BEST1 mutations in Chinese patients with Best vitelliform macular dystrophy[J]. Retina, 2010, 30(5): 820-827. DOI: 10.1097/IAE.0b013e3181c700c1.
12. Querques G, Zerbib J, Santacroce R, et al. The spectrum of subclinical Best vitelliform macular dystrophy in subjects with mutations in BEST1 gene[J]. Invest Ophthalmol Vis Sci, 2011, 52(7): 4678-4684. DOI: 10.1167/iovs.10-6500.
13. Mullins RF, Oh KT, Heffron E, et al. Late development of vitelliform lesions and flecks in a patient with best disease: clinicopathologic correlation[J]. Arch Ophthalmol, 2005, 123(11): 1588-1594.DOI: 10.1001/archopht.123.11.1588.
14. Kramer F, White K, Pauleikhoff D, et al. Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration[J]. Eur J Hum Genet, 2000, 8(4): 286-292. DOI: 10.1038/sj.ejhg.5200447.
15. Kinnick TR, Mullins RF, Dev S, et al. Autosomal recessive vitelliform macular dystrophy in a large cohort of vitelliform macular dystrophy patients[J]. Retina, 2011, 31(3): 581-595. DOI: 10.1097/IAE.0b013e318203ee60.
16. Huang X, Xiao X, Jia X, et al. Mutation analysis of the genes associated with anterior segment dysgenesis, microcornea and microphthalmia in 257 patients with glaucoma[J]. Int J Mol Med, 2015, 36(4): 1111-1117. DOI: 10.3892/ijmm.2015.2325.
17. Lin Y, Gao H, Liu Y, et al. Two novel mutations in the bestrophin-1 gene and associated clinical observations in patients with best vitelliform macular dystrophy[J]. Mol Med Rep, 2015, 12(2): 2584-2588. DOI: 10.3892/mmr.2015.3711.
18. Blodi CF, Stone EM. Best's vitelliform dystrophy[J]. Ophthalmic Paediatr Genet, 1990, 11(1): 49-59.
19. Esfahani MR, Esfahani HR, Mahmoudi A, et al. Focal choroidal excavation in Best vitelliform macular dystrophy: case report[J]. J Clin Diagn Res, 2015, 9(5): 1-2.DOI: 10.7860/JCDR/2015/12861.5993.
20. Liu J, Zhang Y, Xuan Y, et al. Novel BEST1 mutations and special clinical features of Best vitelliform macular dystrophy[J]. Ophthalmic Res, 2016, 56(4): 178-185. DOI: 10.1159/000444681.
21. Rosenthal R, Heimann H, Agostini H, et al. Ca²⁺ channels in retinal pigment epithelial cells regulate vascular endothelial growth factor secretion rates in health and disease[J]. Mol Vis, 2007, 13: 443-456.
22. Quigley HA, Friedman DS, Congdon NG. Possible mechanisms of primary angle-closure and malignant glaucoma[J]. J Glaucoma, 2003, 12(2): 167-180.
23. Zhong Y, Guo X, Xiao H, et al. Flat anterior chamber after trabeculectomy in secondary angle-closure glaucoma with BEST1 gene mutation: case series[J/OL]. PLoS One, 2017, 12(1): 0169395[2017-01-05].https://doi.org/10.1371/journal.pone.0169395. DOI: 10.1371/journal.pone.0169395.

Chinese Journal of Ocular Fundus Diseases

Analysis of BEST1 gene mutations and clinical features in multifocal vitelliform retinopathy patients

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