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

Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Ophthalmic Diseases, Shanghai Key Laboratory of Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China;

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

Video：

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Mutations in the BEST1 gene are associated with a range of retinal diseases collectively referred to as "Best diseases", including Best vitelline macular dystrophy. More than 300 mutations at different sites of the BEST1 gene have been found, which may cause a series of functional disorders such as the mistransport of the calcium-activated anion channel protein-1 protein encoded by it, protein oligomerization defects, and abnormal anion channel activity, leading to different clinical phenotypes. Although it has been established that the BEST1 gene mutation is associated with at least one different type of Best disease, the relationship between the specific gene mutation site and the specific clinical phenotype has not been fully defined. For the time being. Drugs and gene therapy for the Best diseases are still in the basic research stage, which provides a broad development space for future treatment exploration. In the future, when selecting gene therapy in clinical applications, it is necessary to combine the clinical phenotype and molecular diagnosis of patients, and clearly define their mutation types and pathogenic mechanisms in order to achieve better personalized treatment effects.

Citation： Zhang Haoliang, Li Tong, Sun Xiaodong. Research progress in research on Bestrophinopathies and mutations in BEST1 gene. Chinese Journal of Ocular Fundus Diseases, 2025, 41(3): 239-248. doi: 10.3760/cma.j.cn511434-20240909-00335 Copy

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: 347-359.
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.
14.	Tsunenari T, Sun H, Williams J, et al. Structure-function analysis of the bestrophin family of anion channels[J]. J Biol Chem, 2003, 278(42): 41114-41125. DOI: 10.1074/jbc.M306150200.
15.	Vaisey G, Miller AN, Long SB. Distinct regions that control ion selectivity and calcium-dependent activation in the bestrophin ion channel[J]. Proc Natl Acad Sci USA, 2016, 113(47): 7399-7408. DOI: 10.1073/pnas.1614688113.
16.	Kane Dickson V, Pedi L, Long SB. Structure and insights into the function of a Ca(2+)-activated Cl(-) channel[J]. Nature, 2014, 516(7530): 213-218. DOI: 10.1038/nature13913.
17.	Yang T, Liu Q, Kloss B, et al. Structure and selectivity in bestrophin ion channels[J]. Science, 2014, 346(6207): 355-359. DOI: 10.1126/science.1259723.
18.	Doumanov JA, Mladenova K, Moskova-Doumanova V, et al. Self-organization and surface properties of hBest1 in models of biological membranes[J/OL]. Adv Colloid Interface Sci, 2022, 302: 102619[2022-02-22]. https://pubmed.ncbi.nlm.nih.gov/35276535/. DOI: 10.1016/j.cis.2022.102619.
19.	Johnson AA, Guziewicz KE, Lee CJ, et al. Bestrophin 1 and retinal disease[J]. Prog Retin Eye Res, 2017, 58: 45-69. DOI: 10.1016/j.preteyeres.2017.01.006.
20.	Qu Z, Fischmeister R, Hartzell C. Mouse bestrophin-2 is a bona fide Cl(-) channel: identification of a residue important in anion binding and conduction[J]. J Gen Physiol, 2004, 123(4): 327-340. DOI: 10.1085/jgp.200409031.
21.	Qu Z, Hartzell C. Determinants of anion permeation in the second transmembrane domain of the mouse bestrophin-2 chloride channel[J]. J Gen Physiol, 2004, 124(4): 371-382. DOI: 10.1085/jgp.200409108.
22.	Chien LT, Zhang ZR, Hartzell HC. Single Cl- channels activated by Ca2+ in Drosophila S2 cells are mediated by bestrophins[J]. J Gen Physiol, 2006, 128(3): 247-259. DOI: 10.1085/jgp.200609581.
23.	Miller AN, Vaisey G, Long SB. Molecular mechanisms of gating in the calcium-activated chloride channel bestrophin[J/OL]. Elife, 2019, 8: e43231[2019-01-10]. https://pubmed.ncbi.nlm.nih.gov/30628889/. DOI: 10.7554/eLife.43231.
24.	Li Y, Zhang Y, Xu Y, et al. Patient-specific mutations impair BESTROPHIN1's essential role in mediating Ca²⁺-dependent Cl^- currents in human RPE[J/OL]. Elife, 2017, 6: e29914[2017-10-24]. https://pubmed.ncbi.nlm.nih.gov/29063836/. DOI: 10.7554/eLife.29914.
25.	Ji C, Kittredge A, Hopiavuori A, et al. Dual Ca²⁺-dependent gates in human Bestrophin1 underlie disease-causing mechanisms of gain-of-function mutations[J]. Commun Biol, 2019, 2: 240. DOI: 10.1038/s42003-019-0433-3.
26.	Owji AP, Kittredge A, Zhang Y, et al. Structure and Function of the Bestrophin family of calcium-activated chloride channels[J]. Channels (Austin), 2021, 15(1): 604-623. DOI: 10.1080/19336950.2021.1981625.
27.	Xiao Q, Prussia A, Yu K, et al. Regulation of bestrophin Cl channels by calcium: role of the C terminus[J]. J Gen Physiol, 2008, 132(6): 681-692. DOI: 10.1085/jgp.200810056.
28.	Moshfegh Y, Velez G, Li Y, et al. BESTROPHIN1 mutations cause defective chloride conductance in patient stem cell-derived RPE[J]. Hum Mol Genet, 2016, 25(13): 2672-2680. DOI: 10.1093/hmg/ddw126.
29.	Qu Z, Hartzell HC. Bestrophin Cl- channels are highly permeable to HCO3[J]. Am J Physiol Cell Physiol, 2008, 294(6): 1371-1377. DOI: 10.1152/ajpcell.00398.2007.
30.	Sun H, Tsunenari T, Yau KW, et al. The vitelliform macular dystrophy protein defines a new family of chloride channels[J]. Proc Natl Acad Sci USA, 2002, 99(6): 4008-4013. DOI: 10.1073/pnas.052692999.
31.	Pifferi S, Dibattista M, Sagheddu C, et al. Calcium-activated chloride currents in olfactory sensory neurons from mice lacking bestrophin-2[J]. J Physiol, 2009, 587(17): 4265-4279. DOI: 10.1113/jphysiol.2009.176131.
32.	O'Driscoll KE, Hatton WJ, Burkin HR, et al. Expression, localization, and functional properties of Bestrophin 3 channel isolated from mouse heart[J]. Am J Physiol Cell Physiol, 2008, 295(6): 1610-1624. DOI: 10.1152/ajpcell.00461.2008.
33.	Owji AP, Zhao Q, Ji C, et al. Structural and functional characterization of the bestrophin-2 anion channel[J]. Nat Struct Mol Biol, 2020, 27(4): 382-391. DOI: 10.1038/s41594-020-0402-z.
34.	Qu Z, Wei RW, Mann W, et al. Two bestrophins cloned from Xenopus laevis oocytes express Ca²⁺-activated Cl- currents[J]. J Biol Chem, 2003, 278(49): 49563-49572. DOI: 10.1074/jbc.M308414200.
35.	Marmorstein LY, McLaughlin PJ, Stanton JB, et al. Bestrophin interacts physically and functionally with protein phosphatase 2A[J]. J Biol Chem, 2002, 277(34): 30591-30597. DOI: 10.1074/jbc.M204269200.
36.	Rosenthal R, Bakall B, Kinnick T, et al. Expression of bestrophin-1, the product of the VMD2 gene, modulates voltage-dependent Ca²⁺ channels in retinal pigment epithelial cells[J]. FASEB J, 2006, 20(1): 178-180. DOI: 10.1096/fj.05-4495fje.
37.	Yu K, Xiao Q, Cui G, et al. The best disease-linked Cl- channel hBest1 regulates Ca V 1 (L-type) Ca2+ channels via src-homology-binding domains[J]. J Neurosci, 2008, 28(22): 5660-5670. DOI: 10.1523/JNEUROSCI.0065-08.2008.
38.	Milenkovic VM, Krejcova S, Reichhart N, et al. Interaction of bestrophin-1 and Ca2+ channel β-subunits: identification of new binding domains on the bestrophin-1 C-terminus[J/OL]. PLoS One, 2011, 6(4): e19364[2011-04-29]. https://pubmed.ncbi.nlm.nih.gov/21559412/. DOI: 10.1371/journal.pone.0019364.
39.	Reichhart N, Milenkovic VM, Halsband CA, et al. Effect of bestrophin-1 on L-type Ca2+ channel activity depends on the Ca²⁺ channel beta-subunit[J]. Exp Eye Res, 2010, 91(5): 630-639. DOI: 10.1016/j.exer.2010.08.001.
40.	Gómez NM, Tamm ER, Strauβ O. Role of bestrophin-1 in store-operated calcium entry in retinal pigment epithelium[J]. Pflugers Arch, 2013, 465(4): 481-495. DOI: 10.1007/s00424-012-1181-0.
41.	Neussert R, Müller C, Milenkovic VM, et al. The presence of bestrophin-1 modulates the Ca2+ recruitment from Ca2+ stores in the ER[J]. Pflugers Arch, 2010, 460(1): 163-175. DOI: 10.1007/s00424-010-0840-2.
42.	Strauß O, Müller C, Reichhart N, et al. The role of bestrophin-1 in intracellular Ca(2+) signaling[J]. Adv Exp Med Biol, 2014, 801: 113-119. DOI: 10.1007/978-1-4614-3209-8_15.
43.	Zhang Y, Kittredge A, Ward N, et al. ATP activates bestrophin ion channels through direct interaction[J]. Nat Commun, 2018, 9(1): 3126. DOI: 10.1038/s41467-018-05616-4.
44.	Yardley J, Leroy BP, Hart-Holden N, et al. Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC)[J]. Invest Ophthalmol Vis Sci, 2004, 45(10): 3683-3689. DOI: 10.1167/iovs.04-0550.
45.	Wang Y, Jiang Y, Li X, et al. Genetic and clinical features of BEST1-associated retinopathy based on 59 Chinese families and database comparisons[J/OL]. Exp Eye Res, 2022, 223: 109217[2022-08-13]. https://pubmed.ncbi.nlm.nih.gov/35973442/. DOI: 10.1016/j.exer.2022.109217.
46.	Xuan Y, Zhang Y, Zong Y, et al. The clinical features and genetic spectrum of a large cohort of Chinese patients with vitelliform macular dystrophies[J]. Am J Ophthalmol, 2020, 216: 69-79. DOI: 10.1016/j.ajo.2020.03.047.
47.	Gao FJ, Qi YH, Hu FY, et al. Mutation spectrum of the bestrophin-1 gene in a large Chinese cohort with bestrophinopathy[J]. Br J Ophthalmol, 2020, 104(6): 846-851. DOI: 10.1136/bjophthalmol-2019-314679.
48.	Guo J, Gao F, Tang W, et al. Novel Best1 mutations detected by next-generation sequencing in a Chinese population with vitelliform macular dystrophy[J]. Retina, 2019, 39(8): 1613-1622. DOI: 10.1097/IAE.0000000000002183.
49.	Yang S, Li Z, Cheng W, et al. BEST1 novel mutation causes Bestrophinopathies in six families with distinct phenotypic diversity[J/OL]. Mol Genet Genomic Med, 2023, 11(1): e2095[2022-11-15]. https://pubmed.ncbi.nlm.nih.gov/36378562/. DOI: 10.1002/mgg3.2095.
50.	Laich Y, Georgiou M, Fujinami K, et al. Best vitelliform macular dystrophy natural history study report 1: clinical features and genetic findings[J]. Ophthalmology, 2024, 131(7): 845-854. DOI: 10.1016/j.ophtha.2024.01.027.
51.	Nowomiejska K, Nasser F, Stingl K, et al. Disease expression caused by different variants in the BEST1 gene: genotype and phenotype findings in bestrophinopathies[J/OL]. Acta Ophthalmol, 2022, 100(3): e847-e858[2021-07-29]. https://pubmed.ncbi.nlm.nih.gov/34327816/. DOI: 10.1111/aos.14958.
52.	Zhao D, Gu VY, Wang Y, et al. Clinical and genetic features in autosomal recessive bestrophinopathy in Chinese cohort[J]. BMC Ophthalmol, 2024, 24(1): 308. DOI: 10.1186/s12886-024-03574-8.
53.	Tian L, Sun T, Xu K, et al. Screening of BEST1 gene in a Chinese cohort with best vitelliform macular dystrophy or autosomal recessive bestrophinopathy[J]. Invest Ophthalmol Vis Sci, 2017, 58(9): 3366-3375. DOI: 10.1167/iovs.17-21999.
54.	Sodi A, Passerini I, Murro V, et al. BEST1 sequence variants in Italian patients with vitelliform macular dystrophy[J]. Mol Vis, 2012, 18: 2736-2748.
55.	Lin S, Vermeirsch S, Pontikos N, et al. Spectrum of genetic variants in the most common genes causing inherited retinal disease in a large molecularly characterized United Kingdom cohort[J]. Ophthalmol Retina, 2024, 8(7): 699-709. DOI: 10.1016/j.oret.2024.01.012.
56.	Hu F, Li Q, Shi J, et al. Paradoxical autosomal recessive bestrophinopathy-like phenotypes shown in an autosomal dominant pedigree[J]. Eur J Ophthalmol, 2023, 33(6): 2131-2138. DOI: 10.1177/11206721231167767.
57.	Bitner H, Schatz P, Mizrahi-Meissonnier L, et al. Frequency, genotype, and clinical spectrum of best vitelliform macular dystrophy: data from a national center in Denmark[J]. Am J Ophthalmol, 2012, 154(2): 403-412. DOI: 10.1016/j.ajo.2012.02.036.
58.	Bianco L, Arrigo A, Antropoli A, et al. The retinal phenotype associated with the p. Pro101Thr BEST1 variant[J]. Ophthalmol Retina, 2024, 8(3): 288-297. DOI: 10.1016/j.oret.2023.09.012.
59.	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.
60.	Xiao Q, Hartzell HC, Yu K. Bestrophins and retinopathies[J]. Pflugers Arch, 2010, 460(2): 559-569. DOI: 10.1007/s00424-010-0821-5.
61.	Johnson AA, Lee YS, Chadburn AJ, et al. Disease-causing mutations associated with four bestrophinopathies exhibit disparate effects on the localization, but not the oligomerization, of Bestrophin-1[J]. Exp Eye Res, 2014, 121: 74-85. DOI: 10.1016/j.exer.2014.02.006.
62.	Johnson AA, Bachman LA, Gilles BJ, et al. Autosomal recessive bestrophinopathy is not associated with the loss of Bestrophin-1 anion channel function in a patient with a novel BEST1 mutation[J]. Invest Ophthalmol Vis Sci, 2015, 56(8): 4619-4630. DOI: 10.1167/iovs.15-16910.
63.	Nachtigal AL, Milenkovic A, Brandl C, et al. Mutation-dependent pathomechanisms determine the phenotype in the bestrophinopathies[J]. Int J Mol Sci, 2020, 21(5): 1597. DOI: 10.3390/ijms21051597.
64.	Carter DA, Smart MJ, Letton WV, et al. Mislocalisation of BEST1 in iPSC-derived retinal pigment epithelial cells from a family with autosomal dominant vitreoretinochoroidopathy (ADVIRC)[J/OL]. Sci Rep, 2016, 6: 33792[2016-09-22]. https://pubmed.ncbi.nlm.nih.gov/27653836/. DOI: 10.1038/srep33792.
65.	Johnson AA, Lee YS, Stanton JB, et al. Differential effects of Best disease causing missense mutations on bestrophin-1 trafficking[J]. Hum Mol Genet, 2013, 22(23): 4688-4697. DOI: 10.1093/hmg/ddt316.
66.	Davidson AE, Millar ID, Burgess-Mullan R, et al. Functional characterization of bestrophin-1 missense mutations associated with autosomal recessive bestrophinopathy[J]. Invest Ophthalmol Vis Sci, 2011, 52(6): 3730-3736. DOI: 10.1167/iovs.10-6707.
67.	Marmorstein AD, Stanton JB, Yocom J, et al. A model of best vitelliform macular dystrophy in rats[J]. Invest Ophthalmol Vis Sci, 2004, 45(10): 3733-3739. DOI: 10.1167/iovs.04-0307.
68.	Brandl C, Zimmermann SJ, Milenkovic VM, et al. In-depth characterisation of eetinal pigment epithelium (RPE) cells derived from human induced pluripotent stem cells (hiPSC)[J]. Neuromolecular Med, 2014, 16(3): 551-564. DOI: 10.1007/s12017-014-8308-8.
69.	Gouras P, Braun K, Ivert L, et al. Bestrophin detected in the basal membrane of the retinal epithelium and drusen of monkeys with drusenoid maculopathy[J]. Graefe's Arch Clin Exp Ophthalmol, 2009, 247(8): 1051-1056. DOI: 10.1007/s00417-009-1091-9.
70.	Zhao Q, Kong Y, Kittredge A, et al. Distinct expression requirements and rescue strategies for BEST1 loss- and gain-of-function mutations[J/OL]. Elife, 2021, 10: e67622[2021-06-01]. https://pubmed.ncbi.nlm.nih.gov/34061021/. DOI: 10.7554/eLife.67622.
71.	Guziewicz KE, Zangerl B, Lindauer SJ, et al. Bestrophin gene mutations cause canine multifocal retinopathy: a novel animal model for best disease[J]. Invest Ophthalmol Vis Sci, 2007, 48(5): 1959-1967. DOI: 10.1167/iovs.06-1374.
72.	Hoffmann I, Guziewicz KE, Zangerl B, et al. Canine multifocal retinopathy in the Australian Shepherd: a case report[J]. Vet Ophthalmol, 2012, 15(2): 134-138. DOI: 10.1111/j.1463-5224.2012.01005.x.
73.	Zangerl B, Wickström K, Slavik J, et al. Assessment of canine BEST1 variations identifies new mutations and establishes an independent bestrophinopathy model (cmr3)[J]. Mol Vis, 2010, 16: 2791-2804.
74.	Marmorstein LY, Wu J, McLaughlin P, et al. The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1)[J]. J Gen Physiol, 2006, 127(5): 577-589. DOI: 10.1085/jgp.200509473.
75.	Zhang Y, Stanton JB, Wu J, et al. Suppression of Ca2+ signaling in a mouse model of Best disease[J]. Hum Mol Genet, 2010, 19(6): 1108-1118. DOI: 10.1093/hmg/ddp583.
76.	Guziewicz KE, Slavik J, Lindauer SJ, et al. Molecular consequences of BEST1 gene mutations in canine multifocal retinopathy predict functional implications for human bestrophinopathies[J]. Invest Ophthalmol Vis Sci, 2011, 52(7): 4497-4505. DOI: 10.1167/iovs.10-6385.
77.	Guziewicz KE, Aguirre GD, Zangerl B. Modeling the structural consequences of BEST1 missense mutations[J]. Adv Exp Med Biol, 2012, 723: 611-618. DOI: 10.1007/978-1-4614-0631-0_78.
78.	Beltran WA, Cideciyan AV, Guziewicz KE, et al. Canine retina has a primate fovea-like bouquet of cone photoreceptors which is affected by inherited macular degenerations[J/OL]. PLoS One, 2014, 9(3): e90390[2014-03-05]. https://pubmed.ncbi.nlm.nih.gov/24599007/. DOI: 10.1371/journal.pone.0090390.
79.	Guziewicz KE, Zangerl B, Komáromy AM, et al. Recombinant AAV-mediated BEST1 transfer to the retinal pigment epithelium: analysis of serotype-dependent retinal effects[J/OL]. PLoS One, 2013, 8(10): e75666[2013-10-15]. https://pubmed.ncbi.nlm.nih.gov/24143172/. DOI: 10.1371/journal.pone.0075666.
80.	Uggenti C, Briant K, Streit AK, et al. Restoration of mutant bestrophin-1 expression, localisation and function in a polarised epithelial cell model[J]. Dis Model Mech, 2016, 9(11): 1317-1328. DOI: 10.1242/dmm.024216.
81.	Marmorstein AD, Johnson AA, Bachman LA, et al. Mutant Best1 expression and impaired phagocytosis in an iPSC model of autosomal recessive bestrophinopathy[J/OL]. Sci Rep, 2018, 8(1): 4487[2018-03-14]. https://pubmed.ncbi.nlm.nih.gov/29540715/. DOI: 10.1038/s41598-018-21651-z.
82.	Ji C, Li Y, Kittredge A, et al. Investigation and restoration of BEST1 activity in patient-derived RPEs with dominant mutations[J/OL]. Sci Rep, 2019, 9(1): 19026[2019-12-13]. https://pubmed.ncbi.nlm.nih.gov/31836750/. DOI: 10.1038/s41598-019-54892-7.
83.	Sinha D, Steyer B, Shahi PK, et al. Human iPSC modeling reveals mutation-specific responses to gene therapy in a genotypically diverse dominant maculopathy[J]. Am J Hum Genet, 2020, 107(2): 278-292. DOI: 10.1016/j.ajhg.2020.06.011.

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: 347-359.
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.
14. Tsunenari T, Sun H, Williams J, et al. Structure-function analysis of the bestrophin family of anion channels[J]. J Biol Chem, 2003, 278(42): 41114-41125. DOI: 10.1074/jbc.M306150200.
15. Vaisey G, Miller AN, Long SB. Distinct regions that control ion selectivity and calcium-dependent activation in the bestrophin ion channel[J]. Proc Natl Acad Sci USA, 2016, 113(47): 7399-7408. DOI: 10.1073/pnas.1614688113.
16. Kane Dickson V, Pedi L, Long SB. Structure and insights into the function of a Ca(2+)-activated Cl(-) channel[J]. Nature, 2014, 516(7530): 213-218. DOI: 10.1038/nature13913.
17. Yang T, Liu Q, Kloss B, et al. Structure and selectivity in bestrophin ion channels[J]. Science, 2014, 346(6207): 355-359. DOI: 10.1126/science.1259723.
18. Doumanov JA, Mladenova K, Moskova-Doumanova V, et al. Self-organization and surface properties of hBest1 in models of biological membranes[J/OL]. Adv Colloid Interface Sci, 2022, 302: 102619[2022-02-22]. https://pubmed.ncbi.nlm.nih.gov/35276535/. DOI: 10.1016/j.cis.2022.102619.
19. Johnson AA, Guziewicz KE, Lee CJ, et al. Bestrophin 1 and retinal disease[J]. Prog Retin Eye Res, 2017, 58: 45-69. DOI: 10.1016/j.preteyeres.2017.01.006.
20. Qu Z, Fischmeister R, Hartzell C. Mouse bestrophin-2 is a bona fide Cl(-) channel: identification of a residue important in anion binding and conduction[J]. J Gen Physiol, 2004, 123(4): 327-340. DOI: 10.1085/jgp.200409031.
21. Qu Z, Hartzell C. Determinants of anion permeation in the second transmembrane domain of the mouse bestrophin-2 chloride channel[J]. J Gen Physiol, 2004, 124(4): 371-382. DOI: 10.1085/jgp.200409108.
22. Chien LT, Zhang ZR, Hartzell HC. Single Cl- channels activated by Ca2+ in Drosophila S2 cells are mediated by bestrophins[J]. J Gen Physiol, 2006, 128(3): 247-259. DOI: 10.1085/jgp.200609581.
23. Miller AN, Vaisey G, Long SB. Molecular mechanisms of gating in the calcium-activated chloride channel bestrophin[J/OL]. Elife, 2019, 8: e43231[2019-01-10]. https://pubmed.ncbi.nlm.nih.gov/30628889/. DOI: 10.7554/eLife.43231.
24. Li Y, Zhang Y, Xu Y, et al. Patient-specific mutations impair BESTROPHIN1's essential role in mediating Ca²⁺-dependent Cl^- currents in human RPE[J/OL]. Elife, 2017, 6: e29914[2017-10-24]. https://pubmed.ncbi.nlm.nih.gov/29063836/. DOI: 10.7554/eLife.29914.
25. Ji C, Kittredge A, Hopiavuori A, et al. Dual Ca²⁺-dependent gates in human Bestrophin1 underlie disease-causing mechanisms of gain-of-function mutations[J]. Commun Biol, 2019, 2: 240. DOI: 10.1038/s42003-019-0433-3.
26. Owji AP, Kittredge A, Zhang Y, et al. Structure and Function of the Bestrophin family of calcium-activated chloride channels[J]. Channels (Austin), 2021, 15(1): 604-623. DOI: 10.1080/19336950.2021.1981625.
27. Xiao Q, Prussia A, Yu K, et al. Regulation of bestrophin Cl channels by calcium: role of the C terminus[J]. J Gen Physiol, 2008, 132(6): 681-692. DOI: 10.1085/jgp.200810056.
28. Moshfegh Y, Velez G, Li Y, et al. BESTROPHIN1 mutations cause defective chloride conductance in patient stem cell-derived RPE[J]. Hum Mol Genet, 2016, 25(13): 2672-2680. DOI: 10.1093/hmg/ddw126.
29. Qu Z, Hartzell HC. Bestrophin Cl- channels are highly permeable to HCO3[J]. Am J Physiol Cell Physiol, 2008, 294(6): 1371-1377. DOI: 10.1152/ajpcell.00398.2007.
30. Sun H, Tsunenari T, Yau KW, et al. The vitelliform macular dystrophy protein defines a new family of chloride channels[J]. Proc Natl Acad Sci USA, 2002, 99(6): 4008-4013. DOI: 10.1073/pnas.052692999.
31. Pifferi S, Dibattista M, Sagheddu C, et al. Calcium-activated chloride currents in olfactory sensory neurons from mice lacking bestrophin-2[J]. J Physiol, 2009, 587(17): 4265-4279. DOI: 10.1113/jphysiol.2009.176131.
32. O'Driscoll KE, Hatton WJ, Burkin HR, et al. Expression, localization, and functional properties of Bestrophin 3 channel isolated from mouse heart[J]. Am J Physiol Cell Physiol, 2008, 295(6): 1610-1624. DOI: 10.1152/ajpcell.00461.2008.
33. Owji AP, Zhao Q, Ji C, et al. Structural and functional characterization of the bestrophin-2 anion channel[J]. Nat Struct Mol Biol, 2020, 27(4): 382-391. DOI: 10.1038/s41594-020-0402-z.
34. Qu Z, Wei RW, Mann W, et al. Two bestrophins cloned from Xenopus laevis oocytes express Ca²⁺-activated Cl- currents[J]. J Biol Chem, 2003, 278(49): 49563-49572. DOI: 10.1074/jbc.M308414200.
35. Marmorstein LY, McLaughlin PJ, Stanton JB, et al. Bestrophin interacts physically and functionally with protein phosphatase 2A[J]. J Biol Chem, 2002, 277(34): 30591-30597. DOI: 10.1074/jbc.M204269200.
36. Rosenthal R, Bakall B, Kinnick T, et al. Expression of bestrophin-1, the product of the VMD2 gene, modulates voltage-dependent Ca²⁺ channels in retinal pigment epithelial cells[J]. FASEB J, 2006, 20(1): 178-180. DOI: 10.1096/fj.05-4495fje.
37. Yu K, Xiao Q, Cui G, et al. The best disease-linked Cl- channel hBest1 regulates Ca V 1 (L-type) Ca2+ channels via src-homology-binding domains[J]. J Neurosci, 2008, 28(22): 5660-5670. DOI: 10.1523/JNEUROSCI.0065-08.2008.
38. Milenkovic VM, Krejcova S, Reichhart N, et al. Interaction of bestrophin-1 and Ca2+ channel β-subunits: identification of new binding domains on the bestrophin-1 C-terminus[J/OL]. PLoS One, 2011, 6(4): e19364[2011-04-29]. https://pubmed.ncbi.nlm.nih.gov/21559412/. DOI: 10.1371/journal.pone.0019364.
39. Reichhart N, Milenkovic VM, Halsband CA, et al. Effect of bestrophin-1 on L-type Ca2+ channel activity depends on the Ca²⁺ channel beta-subunit[J]. Exp Eye Res, 2010, 91(5): 630-639. DOI: 10.1016/j.exer.2010.08.001.
40. Gómez NM, Tamm ER, Strauβ O. Role of bestrophin-1 in store-operated calcium entry in retinal pigment epithelium[J]. Pflugers Arch, 2013, 465(4): 481-495. DOI: 10.1007/s00424-012-1181-0.
41. Neussert R, Müller C, Milenkovic VM, et al. The presence of bestrophin-1 modulates the Ca2+ recruitment from Ca2+ stores in the ER[J]. Pflugers Arch, 2010, 460(1): 163-175. DOI: 10.1007/s00424-010-0840-2.
42. Strauß O, Müller C, Reichhart N, et al. The role of bestrophin-1 in intracellular Ca(2+) signaling[J]. Adv Exp Med Biol, 2014, 801: 113-119. DOI: 10.1007/978-1-4614-3209-8_15.
43. Zhang Y, Kittredge A, Ward N, et al. ATP activates bestrophin ion channels through direct interaction[J]. Nat Commun, 2018, 9(1): 3126. DOI: 10.1038/s41467-018-05616-4.
44. Yardley J, Leroy BP, Hart-Holden N, et al. Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC)[J]. Invest Ophthalmol Vis Sci, 2004, 45(10): 3683-3689. DOI: 10.1167/iovs.04-0550.
45. Wang Y, Jiang Y, Li X, et al. Genetic and clinical features of BEST1-associated retinopathy based on 59 Chinese families and database comparisons[J/OL]. Exp Eye Res, 2022, 223: 109217[2022-08-13]. https://pubmed.ncbi.nlm.nih.gov/35973442/. DOI: 10.1016/j.exer.2022.109217.
46. Xuan Y, Zhang Y, Zong Y, et al. The clinical features and genetic spectrum of a large cohort of Chinese patients with vitelliform macular dystrophies[J]. Am J Ophthalmol, 2020, 216: 69-79. DOI: 10.1016/j.ajo.2020.03.047.
47. Gao FJ, Qi YH, Hu FY, et al. Mutation spectrum of the bestrophin-1 gene in a large Chinese cohort with bestrophinopathy[J]. Br J Ophthalmol, 2020, 104(6): 846-851. DOI: 10.1136/bjophthalmol-2019-314679.
48. Guo J, Gao F, Tang W, et al. Novel Best1 mutations detected by next-generation sequencing in a Chinese population with vitelliform macular dystrophy[J]. Retina, 2019, 39(8): 1613-1622. DOI: 10.1097/IAE.0000000000002183.
49. Yang S, Li Z, Cheng W, et al. BEST1 novel mutation causes Bestrophinopathies in six families with distinct phenotypic diversity[J/OL]. Mol Genet Genomic Med, 2023, 11(1): e2095[2022-11-15]. https://pubmed.ncbi.nlm.nih.gov/36378562/. DOI: 10.1002/mgg3.2095.
50. Laich Y, Georgiou M, Fujinami K, et al. Best vitelliform macular dystrophy natural history study report 1: clinical features and genetic findings[J]. Ophthalmology, 2024, 131(7): 845-854. DOI: 10.1016/j.ophtha.2024.01.027.
51. Nowomiejska K, Nasser F, Stingl K, et al. Disease expression caused by different variants in the BEST1 gene: genotype and phenotype findings in bestrophinopathies[J/OL]. Acta Ophthalmol, 2022, 100(3): e847-e858[2021-07-29]. https://pubmed.ncbi.nlm.nih.gov/34327816/. DOI: 10.1111/aos.14958.
52. Zhao D, Gu VY, Wang Y, et al. Clinical and genetic features in autosomal recessive bestrophinopathy in Chinese cohort[J]. BMC Ophthalmol, 2024, 24(1): 308. DOI: 10.1186/s12886-024-03574-8.
53. Tian L, Sun T, Xu K, et al. Screening of BEST1 gene in a Chinese cohort with best vitelliform macular dystrophy or autosomal recessive bestrophinopathy[J]. Invest Ophthalmol Vis Sci, 2017, 58(9): 3366-3375. DOI: 10.1167/iovs.17-21999.
54. Sodi A, Passerini I, Murro V, et al. BEST1 sequence variants in Italian patients with vitelliform macular dystrophy[J]. Mol Vis, 2012, 18: 2736-2748.
55. Lin S, Vermeirsch S, Pontikos N, et al. Spectrum of genetic variants in the most common genes causing inherited retinal disease in a large molecularly characterized United Kingdom cohort[J]. Ophthalmol Retina, 2024, 8(7): 699-709. DOI: 10.1016/j.oret.2024.01.012.
56. Hu F, Li Q, Shi J, et al. Paradoxical autosomal recessive bestrophinopathy-like phenotypes shown in an autosomal dominant pedigree[J]. Eur J Ophthalmol, 2023, 33(6): 2131-2138. DOI: 10.1177/11206721231167767.
57. Bitner H, Schatz P, Mizrahi-Meissonnier L, et al. Frequency, genotype, and clinical spectrum of best vitelliform macular dystrophy: data from a national center in Denmark[J]. Am J Ophthalmol, 2012, 154(2): 403-412. DOI: 10.1016/j.ajo.2012.02.036.
58. Bianco L, Arrigo A, Antropoli A, et al. The retinal phenotype associated with the p. Pro101Thr BEST1 variant[J]. Ophthalmol Retina, 2024, 8(3): 288-297. DOI: 10.1016/j.oret.2023.09.012.
59. 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.
60. Xiao Q, Hartzell HC, Yu K. Bestrophins and retinopathies[J]. Pflugers Arch, 2010, 460(2): 559-569. DOI: 10.1007/s00424-010-0821-5.
61. Johnson AA, Lee YS, Chadburn AJ, et al. Disease-causing mutations associated with four bestrophinopathies exhibit disparate effects on the localization, but not the oligomerization, of Bestrophin-1[J]. Exp Eye Res, 2014, 121: 74-85. DOI: 10.1016/j.exer.2014.02.006.
62. Johnson AA, Bachman LA, Gilles BJ, et al. Autosomal recessive bestrophinopathy is not associated with the loss of Bestrophin-1 anion channel function in a patient with a novel BEST1 mutation[J]. Invest Ophthalmol Vis Sci, 2015, 56(8): 4619-4630. DOI: 10.1167/iovs.15-16910.
63. Nachtigal AL, Milenkovic A, Brandl C, et al. Mutation-dependent pathomechanisms determine the phenotype in the bestrophinopathies[J]. Int J Mol Sci, 2020, 21(5): 1597. DOI: 10.3390/ijms21051597.
64. Carter DA, Smart MJ, Letton WV, et al. Mislocalisation of BEST1 in iPSC-derived retinal pigment epithelial cells from a family with autosomal dominant vitreoretinochoroidopathy (ADVIRC)[J/OL]. Sci Rep, 2016, 6: 33792[2016-09-22]. https://pubmed.ncbi.nlm.nih.gov/27653836/. DOI: 10.1038/srep33792.
65. Johnson AA, Lee YS, Stanton JB, et al. Differential effects of Best disease causing missense mutations on bestrophin-1 trafficking[J]. Hum Mol Genet, 2013, 22(23): 4688-4697. DOI: 10.1093/hmg/ddt316.
66. Davidson AE, Millar ID, Burgess-Mullan R, et al. Functional characterization of bestrophin-1 missense mutations associated with autosomal recessive bestrophinopathy[J]. Invest Ophthalmol Vis Sci, 2011, 52(6): 3730-3736. DOI: 10.1167/iovs.10-6707.
67. Marmorstein AD, Stanton JB, Yocom J, et al. A model of best vitelliform macular dystrophy in rats[J]. Invest Ophthalmol Vis Sci, 2004, 45(10): 3733-3739. DOI: 10.1167/iovs.04-0307.
68. Brandl C, Zimmermann SJ, Milenkovic VM, et al. In-depth characterisation of eetinal pigment epithelium (RPE) cells derived from human induced pluripotent stem cells (hiPSC)[J]. Neuromolecular Med, 2014, 16(3): 551-564. DOI: 10.1007/s12017-014-8308-8.
69. Gouras P, Braun K, Ivert L, et al. Bestrophin detected in the basal membrane of the retinal epithelium and drusen of monkeys with drusenoid maculopathy[J]. Graefe's Arch Clin Exp Ophthalmol, 2009, 247(8): 1051-1056. DOI: 10.1007/s00417-009-1091-9.
70. Zhao Q, Kong Y, Kittredge A, et al. Distinct expression requirements and rescue strategies for BEST1 loss- and gain-of-function mutations[J/OL]. Elife, 2021, 10: e67622[2021-06-01]. https://pubmed.ncbi.nlm.nih.gov/34061021/. DOI: 10.7554/eLife.67622.
71. Guziewicz KE, Zangerl B, Lindauer SJ, et al. Bestrophin gene mutations cause canine multifocal retinopathy: a novel animal model for best disease[J]. Invest Ophthalmol Vis Sci, 2007, 48(5): 1959-1967. DOI: 10.1167/iovs.06-1374.
72. Hoffmann I, Guziewicz KE, Zangerl B, et al. Canine multifocal retinopathy in the Australian Shepherd: a case report[J]. Vet Ophthalmol, 2012, 15(2): 134-138. DOI: 10.1111/j.1463-5224.2012.01005.x.
73. Zangerl B, Wickström K, Slavik J, et al. Assessment of canine BEST1 variations identifies new mutations and establishes an independent bestrophinopathy model (cmr3)[J]. Mol Vis, 2010, 16: 2791-2804.
74. Marmorstein LY, Wu J, McLaughlin P, et al. The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1)[J]. J Gen Physiol, 2006, 127(5): 577-589. DOI: 10.1085/jgp.200509473.
75. Zhang Y, Stanton JB, Wu J, et al. Suppression of Ca2+ signaling in a mouse model of Best disease[J]. Hum Mol Genet, 2010, 19(6): 1108-1118. DOI: 10.1093/hmg/ddp583.
76. Guziewicz KE, Slavik J, Lindauer SJ, et al. Molecular consequences of BEST1 gene mutations in canine multifocal retinopathy predict functional implications for human bestrophinopathies[J]. Invest Ophthalmol Vis Sci, 2011, 52(7): 4497-4505. DOI: 10.1167/iovs.10-6385.
77. Guziewicz KE, Aguirre GD, Zangerl B. Modeling the structural consequences of BEST1 missense mutations[J]. Adv Exp Med Biol, 2012, 723: 611-618. DOI: 10.1007/978-1-4614-0631-0_78.
78. Beltran WA, Cideciyan AV, Guziewicz KE, et al. Canine retina has a primate fovea-like bouquet of cone photoreceptors which is affected by inherited macular degenerations[J/OL]. PLoS One, 2014, 9(3): e90390[2014-03-05]. https://pubmed.ncbi.nlm.nih.gov/24599007/. DOI: 10.1371/journal.pone.0090390.
79. Guziewicz KE, Zangerl B, Komáromy AM, et al. Recombinant AAV-mediated BEST1 transfer to the retinal pigment epithelium: analysis of serotype-dependent retinal effects[J/OL]. PLoS One, 2013, 8(10): e75666[2013-10-15]. https://pubmed.ncbi.nlm.nih.gov/24143172/. DOI: 10.1371/journal.pone.0075666.
80. Uggenti C, Briant K, Streit AK, et al. Restoration of mutant bestrophin-1 expression, localisation and function in a polarised epithelial cell model[J]. Dis Model Mech, 2016, 9(11): 1317-1328. DOI: 10.1242/dmm.024216.
81. Marmorstein AD, Johnson AA, Bachman LA, et al. Mutant Best1 expression and impaired phagocytosis in an iPSC model of autosomal recessive bestrophinopathy[J/OL]. Sci Rep, 2018, 8(1): 4487[2018-03-14]. https://pubmed.ncbi.nlm.nih.gov/29540715/. DOI: 10.1038/s41598-018-21651-z.
82. Ji C, Li Y, Kittredge A, et al. Investigation and restoration of BEST1 activity in patient-derived RPEs with dominant mutations[J/OL]. Sci Rep, 2019, 9(1): 19026[2019-12-13]. https://pubmed.ncbi.nlm.nih.gov/31836750/. DOI: 10.1038/s41598-019-54892-7.
83. Sinha D, Steyer B, Shahi PK, et al. Human iPSC modeling reveals mutation-specific responses to gene therapy in a genotypically diverse dominant maculopathy[J]. Am J Hum Genet, 2020, 107(2): 278-292. DOI: 10.1016/j.ajhg.2020.06.011.

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Chinese Journal of Ocular Fundus Diseases

Research progress in research on Bestrophinopathies and mutations in BEST1 gene

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