Missense Mutations in a Retinal Pigment Epithelium Protein, Bestrophin-1, Cause Retinitis Pigmentosa
Overview
Authors
Affiliations
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.
Phenotype and genetic spectrum of six Indian patients with bestrophinopathy.
Shakeel A, Bhatt D, Gopal L, Raman R, Rao C, Sripriya S Taiwan J Ophthalmol. 2025; 14(4):602-608.
PMID: 39803400 PMC: 11717330. DOI: 10.4103/tjo.TJO-D-24-00080.
The pentameric chloride channel BEST1 is activated by extracellular GABA.
Pant S, Tam S, Long S bioRxiv. 2024; .
PMID: 39605608 PMC: 11601618. DOI: 10.1101/2024.11.22.624909.
Ion channels research in hPSC-RPE cells: bridging benchwork to clinical applications.
Xu P, Zou W, Yin W, Chen G, Gao G, Zhong X J Transl Med. 2024; 22(1):1073.
PMID: 39604931 PMC: 11600670. DOI: 10.1186/s12967-024-05769-5.
Li J, Meng L, Hou B, Hao X, Wang D, Qu L Curr Med Sci. 2024; 44(2):419-425.
PMID: 38619684 DOI: 10.1007/s11596-024-2865-3.
Beryozkin A, Sher I, Ehrenberg M, Zur D, Newman H, Gradstein L Invest Ophthalmol Vis Sci. 2024; 65(2):39.
PMID: 38411968 PMC: 10910552. DOI: 10.1167/iovs.65.2.39.