Research progress in research on Bestrophinopathies and mutations in <i>BEST1</i> gene_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhang Haoliang ,  Li Tong , Sun Xiaodong

上海交通大学医学院附属第一人民医院眼科国家眼部疾病临床医学研究中心上海市眼底病重点实验室上海眼视觉与光医学工程技术研究中心, 上海 200080;

Corresponding author：

Li Tong, Email: litong_linda@outlook.com

Keywords：

BEST1 gene mutation; Bestrophinopathies; Anion channel; Protein dysfunction; Gene therapy; Review

DOI：

10.3760/cma.j.cn511434-20240909-00335

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Since 1998, BEST1 gene mutations have been reported to cause at least five different clinical phenotypes such as Best vitelline macular dystrophy (BVMD), collectively known as “bestrophinopathies”, for which there is currently no effective treatment. Existing studies have found more than 300 mutations at different sites of the BEST1 gene, which may cause protein dysfunction such as malfunction of transportation, protein oligomerization defects, and abnormal anion channel activity of the encoded bestrophin1 protein, resulting in different manifestations. However, the relationship between the diverse clinical phenotypes of bestrophinopathies and the different mutation sites of BEST1 gene is still unclear. Drugs and gene therapy for bestrophinopathies are still under fundamental research and have a very broad prospect. In the future clinical selection of gene therapy, it is necessary to combine the clinical phenotype and molecular diagnosis of patients, clearly define their mutation types and pathogenic mechanisms, in order to achieve better personalized treatment effects.

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1. Marmorstein AD, Marmorstein LY, Rayborn M, et al. Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium[J]. Proc Natl Acad Sci USA, 2000, 97(23): 12758-12763. DOI: 10.1073/pnas.220402097.
2. Marmorstein AD, Kinnick TR, Stanton JB, et al. Bestrophin-1 influences transepithelial electrical properties and Ca2+ signaling in human retinal pigment epithelium[J]. Mol Vis, 2015, 21: 347-59.
3. Milenkovic A, Brandl C, Milenkovic VM, et al. Bestrophin 1 is indispensable for volume regulation in human retinal pigment epithelium cells[J/OL]. Proc Natl Acad Sci USA, 2015, 112(20): E2630-2639[2015-05-19]. https://pubmed.ncbi.nlm.nih.gov/25941382/. DOI: 10.1073/pnas.1418840112.
4. Singh R, Shen W, Kuai D, et al. iPS cell modeling of Best disease: insights into the pathophysiology of an inherited macular degeneration[J]. Hum Mol Genet, 2013, 22(3): 593-607. DOI: 10.1093/hmg/dds469.
5. Marquardt A, Stöhr H, Passmore LA, et al. Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease)[J]. Hum Mol Genet, 1998, 7(9): 1517-1525. DOI: 10.1093/hmg/7.9.1517.
6. Petrukhin K, Koisti MJ, Bakall B, et al. Identification of the gene responsible for Best macular dystrophy[J]. Nat Genet, 1998, 19(3): 241-247. DOI: 10.1038/915.
7. Aldehni F, Spitzner M, Martins JR, et al. Bestrophin 1 promotes epithelial-to-mesenchymal transition of renal collecting duct cells[J]. J Am Soc Nephrol, 2009, 20(7): 1556-1564. DOI: 10.1681/ASN.2008090987.
8. Barro Soria R, Spitzner M, Schreiber R, et al. Bestrophin-1 enables Ca2+-activated Cl- conductance in epithelia[J]. J Biol Chem, 2009, 284(43): 29405-29412. DOI: 10.1074/jbc.M605716200.
9. Boudes M, Sar C, Menigoz A, et al. Best1 is a gene regulated by nerve injury and required for Ca2+-activated Cl- current expression in axotomized sensory neurons[J]. J Neurosci, 2009, 29(32): 10063-10071. DOI: 10.1523/JNEUROSCI.1312-09.2009.
10. Lee S, Yoon BE, Berglund K, et al. Channel-mediated tonic GABA release from glia[J]. Science, 2010, 330(6005): 790-796. DOI: 10.1126/science.1184334.
11. Spitzner M, Martins JR, Soria RB, et al. Eag1 and Bestrophin 1 are up-regulated in fast-growing colonic cancer cells[J]. J Biol Chem, 2008, 283(12): 7421-7428. DOI: 10.1074/jbc.M703758200.
12. Oh SJ, Lee CJ. Distribution and function of the Bestrophin-1 (Best1) channel in the brain[J]. Exp Neurobiol, 2017, 26(3): 113-121. DOI: 10.5607/en.2017.26.3.113.
13. Milenkovic VM, Rivera A, Horling F, et al. Insertion and topology of normal and mutant bestrophin-1 in the endoplasmic reticulum membrane[J]. J Biol Chem, 2007, 282(2): 1313-1321. DOI: 10.1074/jbc.M607383200.
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