Missense Mutations in a Retinal Pigment Epithelium Protein, Bestrophin-1, Cause Retinitis Pigmentosa

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2009 Oct 27

PMID 19853238

Citations 95

Authors

Alice E Davidson

Ian D Millar

Jill E Urquhart

Rosemary Burgess-Mullan

Yusrah Shweikh

Neil Parry

James OSullivan

Geoffrey J Maher

Martin McKibbin

Susan M Downes

Andrew J Lotery

Samuel G Jacobson

Peter D Brown

Graeme C M Black

Forbes D C Manson

Affiliations

Soon will be listed here.

Abstract

Bestrophin-1 is preferentially expressed at the basolateral membrane of the retinal pigmented epithelium (RPE) of the retina. Mutations in the BEST1 gene cause the retinal dystrophies vitelliform macular dystrophy, autosomal-dominant vitreochoroidopathy, and autosomal-recessive bestrophinopathy. Here, we describe four missense mutations in bestrophin-1, three that we believe are previously unreported, in patients diagnosed with autosomal-dominant and -recessive forms of retinitis pigmentosa (RP). The physiological function of bestrophin-1 remains poorly understood although its heterologous expression induces a Cl--specific current. We tested the effect of RP-causing variants on Cl- channel activity and cellular localization of bestrophin-1. Two (p.L140V and p.I205T) produced significantly decreased chloride-selective whole-cell currents in comparison to those of wild-type protein. In a model system of a polarized epithelium, two of three mutations (p.L140V and p.D228N) caused mislocalization of bestrophin-1 from the basolateral membrane to the cytoplasm. Mutations in bestrophin-1 are increasingly recognized as an important cause of inherited retinal dystrophy.

Citing Articles

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References

Sun H, Tsunenari T, Yau K, Nathans J . The vitelliform macular dystrophy protein defines a new family of chloride channels. Proc Natl Acad Sci U S A. 2002; 99(6):4008-13. PMC: 122639. DOI: 10.1073/pnas.052692999. View

Mendes F, Wakefield J, Bachhuber T, Barroso M, Bebok Z, Penque D . Establishment and characterization of a novel polarized MDCK epithelial cellular model for CFTR studies. Cell Physiol Biochem. 2005; 16(4-6):281-90. DOI: 10.1159/000089857. View

Marmorstein A, Marmorstein L, Rayborn M, Wang X, Hollyfield J, Petrukhin K . Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium. Proc Natl Acad Sci U S A. 2000; 97(23):12758-63. PMC: 18837. DOI: 10.1073/pnas.220402097. View

Milenkovic V, Langmann T, Schreiber R, Kunzelmann K, Weber B . Molecular evolution and functional divergence of the bestrophin protein family. BMC Evol Biol. 2008; 8:72. PMC: 2292144. DOI: 10.1186/1471-2148-8-72. View

Marquardt A, Stohr H, Passmore L, Kramer F, Rivera A, Weber B . Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease). Hum Mol Genet. 1998; 7(9):1517-25. DOI: 10.1093/hmg/7.9.1517. View

Burgess R, Millar I, Leroy B, Urquhart J, Fearon I, De Baere E . Biallelic mutation of BEST1 causes a distinct retinopathy in humans. Am J Hum Genet. 2008; 82(1):19-31. PMC: 2253971. DOI: 10.1016/j.ajhg.2007.08.004. View

Hartzell H, Qu Z, Yu K, Xiao Q, Chien L . Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies. Physiol Rev. 2008; 88(2):639-72. DOI: 10.1152/physrev.00022.2007. View

Rosenthal R, Bakall B, Kinnick T, Peachey N, Wimmers S, Wadelius C . Expression of bestrophin-1, the product of the VMD2 gene, modulates voltage-dependent Ca2+ channels in retinal pigment epithelial cells. FASEB J. 2005; 20(1):178-80. DOI: 10.1096/fj.05-4495fje. View

Milam A, De Castro E, Smith J, Tang W, John S, Gorin M . Concentric retinitis pigmentosa: clinicopathologic correlations. Exp Eye Res. 2002; 73(4):493-508. DOI: 10.1006/exer.2001.1059. View

10.

Pierro L, Tremolada G, Introini U, Calori G, Brancato R . Optical coherence tomography findings in adult-onset foveomacular vitelliform dystrophy. Am J Ophthalmol. 2002; 134(5):675-80. DOI: 10.1016/s0002-9394(02)01685-9. View

11.

Marmorstein A, Cross H, Peachey N . Functional roles of bestrophins in ocular epithelia. Prog Retin Eye Res. 2009; 28(3):206-26. PMC: 2740978. DOI: 10.1016/j.preteyeres.2009.04.004. View

12.

Cordat E . Unraveling trafficking of the kidney anion exchanger 1 in polarized MDCK epithelial cells. Biochem Cell Biol. 2007; 84(6):949-59. DOI: 10.1139/o06-200. View

13.

Yu K, Qu Z, Cui Y, Hartzell H . Chloride channel activity of bestrophin mutants associated with mild or late-onset macular degeneration. Invest Ophthalmol Vis Sci. 2007; 48(10):4694-705. DOI: 10.1167/iovs.07-0301. View

14.

Boon C, den Hollander A, Hoyng C, Cremers F, Klevering B, Keunen J . The spectrum of retinal dystrophies caused by mutations in the peripherin/RDS gene. Prog Retin Eye Res. 2008; 27(2):213-35. DOI: 10.1016/j.preteyeres.2008.01.002. View

15.

Lotery A, Munier F, Fishman G, Weleber R, Jacobson S, Affatigato L . Allelic variation in the VMD2 gene in best disease and age-related macular degeneration. Invest Ophthalmol Vis Sci. 2000; 41(6):1291-6. View

16.

Guziewicz K, Zangerl B, Lindauer S, Mullins R, Sandmeyer L, Grahn B . Bestrophin gene mutations cause canine multifocal retinopathy: a novel animal model for best disease. Invest Ophthalmol Vis Sci. 2007; 48(5):1959-67. PMC: 1931491. DOI: 10.1167/iovs.06-1374. View

17.

Kausalya P, Amasheh S, Gunzel D, Wurps H, Muller D, Fromm M . Disease-associated mutations affect intracellular traffic and paracellular Mg2+ transport function of Claudin-16. J Clin Invest. 2006; 116(4):878-91. PMC: 1395478. DOI: 10.1172/JCI26323. View

18.

Choi J, Muallem D, Kiselyov K, Lee M, Thomas P, Muallem S . Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis. Nature. 2001; 410(6824):94-7. PMC: 3943212. DOI: 10.1038/35065099. View

19.

Bakall B, Marmorstein L, Hoppe G, Peachey N, Wadelius C, Marmorstein A . Expression and localization of bestrophin during normal mouse development. Invest Ophthalmol Vis Sci. 2003; 44(8):3622-8. DOI: 10.1167/iovs.03-0030. View

20.

Pianta M, Aleman T, Cideciyan A, Sunness J, Li Y, Campochiaro B . In vivo micropathology of Best macular dystrophy with optical coherence tomography. Exp Eye Res. 2003; 76(2):203-11. DOI: 10.1016/s0014-4835(02)00280-4. View