Bestrophin 1 and retinal disease

Abstract

Mutations in the gene BEST1 are causally associated with as many as five clinically distinct retinal degenerative diseases, which are collectively referred to as the “bestrophinopathies”. These five associated diseases are: Best vitelliform macular dystrophy, autosomal recessive bestrophinopathy, adult-onset vitelliform macular dystrophy, autosomal dominant vitreoretinochoroidopathy, and retinitis pigmentosa. The most common of these is Best vitelliform macular dystrophy. Bestrophin 1 (Best1), the protein encoded by the gene BEST1, has been the subject of a great deal of research since it was first identified nearly two decades ago. Today we know that Best1 functions as both a pentameric anion channel and a regulator of intracellular Ca2+ signaling. Best1 is an integral membrane protein which, within the eye, is uniquely expressed in the retinal pigment epithelium where it predominantly localizes to the basolateral plasma membrane. Within the brain, Best1 expression has been documented in both glial cells and astrocytes where it functions in both tonic GABA release and glutamate transport. The crystal structure of Best1 has revealed critical information about how Best1 functions as an ion channel and how Ca2+ regulates that function. Studies using animal models have led to critical insights into the physiological roles of Best1 and advances in stem cell technology have allowed for the development of patient-derived, “disease in a dish” models. In this article we review our knowledge of Best1 and discuss prospects for near-term clinical trials to test therapies for the bestrophinopathies, a currently incurable and untreatable set of diseases.

Novel BEST1 gene mutations associated with two different forms of macular dystrophy in Tunisian families

“…More than 250 mutations in the BEST1 gene have been identified and associated at least with five untreatable forms of macular dystrophies: Best vitelliform macular dystrophy (BVMD), autosomal recessive bestrophinopathy (ARB), adult onset vitelliform macular dystrophy, autosomal dominant vitreoretinochoroidopathy and retinitis pigmentosa (http://www.hgmd.cf.ac.uk/ac/gene.php?gene=BEST1). Although this large number of genetic alterations have been identified and linked to retinal degenerative diseases, the pathological mechanisms remain uncertain generally due to (a) the lack of in vivo model for the study of the protein and its mutations under physiological conditions (b) and the difficulty to get human RPE cells .…”

Inhibition of Ca 2+ channel surface expression by mutant bestrophin‐1 in RPE cells

“…Analysis of human retina sections with defined BEST1 mutations verified this patho‐mechanism at the patient's level . The mutation‐dependent loss of basolateral Cl − conductance might explain the reduced light‐peak in the patients' EOG because this signal results from light‐dependent activation of basolateral Cl − channels in the RPE and subsequent depolarization of the basolateral membrane . Furthermore, a direct loss of Cl − and water transport or its disturbed regulation might explain the recently detected microdetachments in the retina of a dog bestrophinopathy model that could be cured by gene therapy .…”

“…With Ca V 1.3, we have investigated one interaction partner of bestrophin‐1. To date, there are more interaction partners of bestrophin‐1 known such as phosphatase PPA2 or NEDD4 . The excellent review by Johnson et al discusses bestrophin‐1 as a multifunctional protein.…”

“…Thus, not only the disturbed interaction of mutant bestrophin‐1 with Ca 2+ channel subunits contributes to the chain of events leading to macular dystrophy. In vivo studies and in vitro studies, however, point toward the idea that this multifunction regulates Ca 2+ signalling in the RPE . Our data further support a role of Ca 2+ signaling in disease.…”

“…Best vitelliform macular dystrophy (BVMD) is an autosomal dominant, progredient visual impairment resulting of mutations in the BEST1 gene . BEST1 encodes bestrophin‐1, a protein mainly localized to the basolateral membrane of the retinal pigment epithelium (RPE) . Since the RPE is a close interaction partner of photoreceptors and responsible for maintaining photoreceptor structure and function, it is hypothesized that mutations in BEST1 lead to impairment of RPE function and subsequently to photoreceptor loss .…”