Autosomal Recessive Bestrophinopathy Is Not Associated With the Loss of Bestrophin-1 Anion Channel Function in a Patient With a Novel<i>BEST1</i>Mutation

Johnson, Adiv A.; Bachman, Lori A.; Gilles, Benjamin; Cross, Samuel D.; Stelzig, K.; Resch, Zachary T.; Marmorstein, Lihua Y.; Pulido, José S.; Marmorstein, Alan D.

doi:10.1167/iovs.15-16910

Cited by 41 publications

(56 citation statements)

References 48 publications

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“…An individual with ARB has been reported with p.R141H and p.D312N (Boon et al, 2013); as discussed above for p.R141H, p.D312N can either be asymptomatic in carriers or act dominantly in individuals with Best disease (Burgess et al, 2008; Sodi et al, 2011), giving the situation where two autosomal dominant mutations occur as compound heterozygous mutations to cause an autosomal recessive disease. Similar confounding combinations with p.R141H have also been reported with p.L41P, p.Y29X, p.P233A and p.I266fsX18 (Burgess et al, 2008; Schatz et al, 2006; Wittström et al, 2011; Johnson et al, 2015). Thus, it would seem that the pathogenic mechanism not only varies from mutation to mutation, but also on what other mutation is present and as-yet-unidentified factors such as promoter strength, modifying genes and environment.…”

Section: Discussionsupporting

confidence: 81%

Restoration of mutant bestrophin-1 expression, localisation and function in a polarised epithelial cell model

Uggenti

Briant

Streit

et al. 2016

Disease Models &Amp; Mechanisms

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Autosomal recessive bestrophinopathy (ARB) is a retinopathy caused by mutations in the bestrophin-1 protein, which is thought to function as a Ca2+-gated Cl− channel in the basolateral surface of the retinal pigment epithelium (RPE). Using a stably transfected polarised epithelial cell model, we show that four ARB mutant bestrophin-1 proteins were mislocalised and subjected to proteasomal degradation. In contrast to the wild-type bestrophin-1, each of the four mutant proteins also failed to conduct Cl− ions in transiently transfected cells as determined by whole-cell patch clamp. We demonstrate that a combination of two clinically approved drugs, bortezomib and 4-phenylbutyrate (4PBA), successfully restored the expression and localisation of all four ARB mutant bestrophin-1 proteins. Importantly, the Cl− conductance function of each of the mutant bestrophin-1 proteins was fully restored to that of wild-type bestrophin-1 by treatment of cells with 4PBA alone. The functional rescue achieved with 4PBA is significant because it suggests that this drug, which is already approved for long-term use in infants and adults, might represent a promising therapy for the treatment of ARB and other bestrophinopathies resulting from missense mutations in BEST1.

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Section: Discussionsupporting

confidence: 81%

Restoration of mutant bestrophin-1 expression, localisation and function in a polarised epithelial cell model

Uggenti

Briant

Streit

et al. 2016

Disease Models &Amp; Mechanisms

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“…Immunohistochemical staining of macaque and porcine eyes showed that this staining was unique to the basolateral plasma membrane and this was confirmed by confocal microscopy (Marmorstein et al, 2000). This RPE-specific ocular expression and/or basolateral plasma membrane localization of Best1 has been confirmed by many subsequent studies using several different native models, including fetal human RPE cells (Johnson et al, 2013; Marmorstein et al, 2015), induced pluripotent stem cell (iPSC)-derived RPE cells (Brandl et al, 2014; Johnson et al, 2015; Milenkovic et al, 2015; Singh et al, 2013), mice (Marmorstein et al, 2006; Zhang et al, 2010), rats (Marmorstein et al, 2004), dogs (Guziewicz et al, 2013), rhesus monkeys (Gouras et al, 2009), and humans (Dalvin et al, 2015; Mullins et al, 2007). Basolateral plasma membrane localization has also been confirmed in models where Best1 was heterologously expressed, namely Madin-darby canine kidney II cells (Davidson et al, 2011; Davidson et al, 2009; Johnson et al, 2014; Johnson et al, 2013; Milenkovic et al, 2011b) and ARPE-19 cells (Marmorstein et al, 2000; Rosenthal et al, 2006).…”

Section: Best1 Expression Localization and Functionmentioning

confidence: 73%

“…There are small vitelliform lesions (Fig. 4A, B) proximal to the arcades (Boon et al, 2009; Johnson et al, 2015; Marmorstein et al, 2009). Yellowish, subretinal deposits are also common fundus findings (Fig.…”

Section: Clinical Spectrum Of the Bestrophinopathiesmentioning

confidence: 99%

“…When co-expressed with Best1 in MDCK cells, both WT and mutant Best1 co-localize together predominantly in intracellular compartments (Johnson et al, 2014). In contrast, Best1 R141H is properly localized to the plasma membrane when expressed via adenovirus-mediated gene transfer in confluent, iPSC-RPE cells (Johnson et al, 2015). That Best1 R141H is properly localized in the presence of endogenous Best1 in iPSC-RPE cells yet mislocalized in the presence of Best1 in heterologous MDCK cells would suggest that trafficking results in MDCK cells should be validated in a native model (i.e., iPSC-RPE, fhRPE).…”

Section: Pathogenesis Of the Bestrophinopathiesmentioning

confidence: 99%

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Bestrophin 1 and retinal disease

Johnson

Guziewicz

Lee

et al. 2017

Progress in Retinal and Eye Research

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196

177

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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.

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“…53 Adenovirus vectors have also been used to deliver BEST1 mutants to iPSC-derived RPE; these studies have defined amino acids needed for channel activity and correct protein localization. 54 iPSC-derived RPE from patients with mutations in the MERTK gene, which causes RP, exhibits defective phagocytosis 55 and from patients with mutations in RP2 shows defects in IFT20 localization, Golgi cohesion, and protein trafficking, which could be corrected either by protein overexpression or by translational read through inducing drugs. 56 iPSC lines from AMD-affected individuals have also been used to derive RPE cells, to model the disease in vitro or for drug screening.…”

Section: Ipsc Retinal Disease Modelingmentioning

confidence: 99%

Induced Pluripotent Stem Cell Therapies for Degenerative Disease of the Outer Retina: Disease Modeling and Cell Replacement

Foggia

Makwana

Ali³

et al. 2016

Journal of Ocular Pharmacology and Therapeutics

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Stem cell therapies are being explored as potential treatments for retinal disease. How to replace neurons in a degenerated retina presents a continued challenge for the regenerative medicine field that, if achieved, could restore sight. The major issues are: (i) the source and availability of donor cells for transplantation; (ii) the differentiation of stem cells into the required retinal cells; and (iii) the delivery, integration, functionality, and survival of new cells in the host neural network. This review considers the use of induced pluripotent stem cells (iPSC), currently under intense investigation, as a platform for cell transplantation therapy. Moreover, patientspecific iPSC are being developed for autologous cell transplantation and as a tool for modeling specific retinal diseases, testing gene therapies, and drug screening.

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Autosomal Recessive Bestrophinopathy Is Not Associated With the Loss of Bestrophin-1 Anion Channel Function in a Patient With a NovelBEST1Mutation

Cited by 41 publications

References 48 publications

Restoration of mutant bestrophin-1 expression, localisation and function in a polarised epithelial cell model

Restoration of mutant bestrophin-1 expression, localisation and function in a polarised epithelial cell model

Bestrophin 1 and retinal disease

Induced Pluripotent Stem Cell Therapies for Degenerative Disease of the Outer Retina: Disease Modeling and Cell Replacement

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