Disease-causing mutations associated with bestrophinopathies promote apoptosis in retinal pigment epithelium cells



Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB) are two kinds of bestrophinopathies which are caused by BEST1 mutations and characterized by accumulation of lipofuscin-like materials on the retinal pigment epithelium cell-photoreceptor interface. In the past two decades, research about the pathogenesis of bestrophinopathies was mainly focused on the anion channel and intracellular Ca2+ signaling, but seldom concentrated on the function of retinal pigment epithelium (RPE) cells. In this study, we explored the possible effect of the three BEST1 mutations p.V143F, p.S142G, and p.A146T on the apoptosis in human fetal RPE cells.


Wild-type plasmid and mutant plasmids BEST1-pcDNA3.1 p.V143F, p.S142G, and p.A146T were transfected to human fetal RPE cells. The molecules caspase-3, phospho-Bcl-2, BAX, PARP, and AIF associated with apoptosis were determined by quantitative PCR and Western blot. Apoptotic rate and active Caspase-3 staining were analyzed by flow cytometry.


Caspase-3 and PARP expression were significantly increased in BEST1-pcDNA3.1 p.S142G and p.A146T group. Flow cytometry showed that the apoptosis rates were significantly increased in the BEST1-pcDNA3.1 p.V143F, p.S142G, and p.A146T group compared with the wild-type group.


For the first time, we found that the three mutations promoted RPE cell apoptosis. Furthermore, the results indicated that BEST1 mutations p.S142G and p.A146T may contribute apoptosis of RPE cells by targeting Caspase 3. Our observations suggested that the apoptosis of RPE cells may be one of the mechanisms in bestrophinopathies, which may provide a new potential therapeutic target for the treatment of this disease.

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This work was supported by the National Natural Science Foundation of China Grant (81470649, 81470651, 81670870), the Beijing Nova Program (Z161100004916058), and Beijing Municipal Science and Technology Project (Z171100002217081). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Correspondence to Lvzhen Huang or Mingwei Zhao.

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The study followed the tenets of the Declaration of Helsinki and was performed in accordance with ethics committee of Peking University People’s Hospital.

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Gao, T., Tian, C., Xu, H. et al. Disease-causing mutations associated with bestrophinopathies promote apoptosis in retinal pigment epithelium cells. Graefes Arch Clin Exp Ophthalmol (2020). https://doi.org/10.1007/s00417-020-04636-5

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  • BEST1 mutation
  • Caspase 3
  • Human retinal pigment epithelium cell
  • Apoptosis
  • Bestrophinopathy
  • Pathogenesis