Long-Term Macular Changes in the First Proband of Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC) Due to a Newly Identified Mutation in<i>BEST1</i>

Chen, Connie J.; Kaufman, Stuart J.; Packo, Kirk H.; Stöhr, Heidi; Weber, Bernhard H. F.

doi:10.3109/13816810.2015.1039893

Cited by 17 publications

(17 citation statements)

References 14 publications

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“…Further studies have shown that there can be a progression of the fundus findings with downstream development of central cone dysfunction. Similar progression in the posterior pole has also been noted (Chen and Goldberg, 2016; Chen et al, 2016; Oh and Vallar, 2006). In 2004, Yardley et al described five families with ADVIRC and nanophthalmos that were genetically linked to mutations in BEST1 (Yardley et al, 2004).…”

Section: Clinical Spectrum Of the Bestrophinopathiessupporting

confidence: 78%

Bestrophin 1 and retinal disease

Johnson

Guziewicz

Lee

et al. 2017

Progress in Retinal and Eye Research

198

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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Section: Clinical Spectrum Of the Bestrophinopathiessupporting

confidence: 78%

Bestrophin 1 and retinal disease

Johnson

Guziewicz

Lee

et al. 2017

Progress in Retinal and Eye Research

198

177

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“…In this system, the c.704T > C (p.V235A) mutation resulted in the duplication of Exon 6 27 . However, recent investigations into a novel mutation (pG83D) using the same minigene assay in HEK293 cells failed to show any effect on splicing 4 . To test the hypothesis that alterations in splicing cause ADVIRC, we assessed transcript expression in iPSC-RPE cells from patients harbouring the pV235A mutation.…”

Section: Discussionmentioning

confidence: 92%

“…Autosomal dominant vitreoretinochoroidopathy (ADVIRC–OMIM 193220) is a rare retinal dystrophy characterised by distinct fundus appearance with a circumferential ring of retinal atrophy and pigmentation in the far peripheral retina 1 2 3 . The macula is usually normal at diagnosis but cystoid macular oedema and macular atrophy may occur over time 4 . Other ocular features include cataract, angle closure glaucoma, fibrillar condensation of the vitreous, retinovascular abnormalities and developmental abnormalities, such as nanophthalmos and microcornea 5 .…”

mentioning

confidence: 99%

“…These findings lead to the hypothesis that ADVIRC is caused by aberrant BEST1 pre-mRNA splicing. However, a recent report, which identified and characterised a novel ADVIRC-associated missense mutation, c.248G > A (p.G83D), in the same minigene system, suggests that aberrant splicing may not account for the ADVIRC phenotype 4 . Ideally, the effects of these mutations should be examined in ADVIRC patient RPE cells, however these tissues are rarely available.…”

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confidence: 99%

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Mislocalisation of BEST1 in iPSC-derived retinal pigment epithelial cells from a family with autosomal dominant vitreoretinochoroidopathy (ADVIRC)

Carter¹,

Smart²,

Letton³

et al. 2016

Sci Rep

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Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is a rare, early-onset retinal dystrophy characterised by distinct bands of circumferential pigmentary degeneration in the peripheral retina and developmental eye defects. ADVIRC is caused by mutations in the Bestrophin1 (BEST1) gene, which encodes a transmembrane protein thought to function as an ion channel in the basolateral membrane of retinal pigment epithelial (RPE) cells. Previous studies suggest that the distinct ADVIRC phenotype results from alternative splicing of BEST1 pre-mRNA. Here, we have used induced pluripotent stem cell (iPSC) technology to investigate the effects of an ADVIRC associated BEST1 mutation (c.704T > C, p.V235A) in patient-derived iPSC-RPE. We found no evidence of alternate splicing of the BEST1 transcript in ADVIRC iPSC-RPE, however in patient-derived iPSC-RPE, BEST1 was expressed at the basolateral membrane and the apical membrane. During human eye development we show that BEST1 is expressed more abundantly in peripheral RPE compared to central RPE and is also expressed in cells of the developing retina. These results suggest that higher levels of mislocalised BEST1 expression in the periphery, from an early developmental stage, could provide a mechanism that leads to the distinct clinical phenotype observed in ADVIRC patients.

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“…These contradictory results could suggest that proper BEST1 localization or a failure to correctly traffic to the cell membrane is rather mutation-dependent than an ADVIRC-specific characteristic and further underscores the necessity to model additional ADVIRC mutations on the basis of the hiPSC-RPE cell culture model. Furthermore, studies have shown that ADVIRC mutations p.(V86M), p.(Y236C), p.(V239M), and p.(V235A) affect BEST1 mRNA splicing using a minigene assay in HEK293 cells [8,46] while ADVIRC mutation p.(G83D) failed to exhibit any effect on mRNA splicing [47]. In the present study, we found no evidence for alternative splicing in the ADVIRC-associated hiPSC-RPE cell lines well in agreement with earlier findings from Carter et al [35].…”

Section: Discussionmentioning

confidence: 99%

Mutation-Dependent Pathomechanisms Determine the Phenotype in the Bestrophinopathies

Nachtigal

Milenkovic

Brandl

et al. 2020

IJMS

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Best vitelliform macular dystrophy (BD), autosomal dominant vitreoretinochoroidopathy (ADVIRC), and the autosomal recessive bestrophinopathy (ARB), together known as the bestrophinopathies, are caused by mutations in the bestrophin-1 (BEST1) gene affecting anion transport through the plasma membrane of the retinal pigment epithelium (RPE). To date, while no treatment exists a better understanding of BEST1-related pathogenesis may help to define therapeutic targets. Here, we systematically characterize functional consequences of mutant BEST1 in thirteen RPE patient cell lines differentiated from human induced pluripotent stem cells (hiPSCs). Both BD and ARB hiPSC-RPEs display a strong reduction of BEST1-mediated anion transport function compared to control, while ADVIRC mutations trigger an increased anion permeability suggesting a stabilized open state condition of channel gating. Furthermore, BD and ARB hiPSC-RPEs differ by the degree of mutant protein turnover and by the site of subcellular protein quality control with adverse effects on lysosomal pH only in the BD-related cell lines. The latter finding is consistent with an altered processing of catalytic enzymes in the lysosomes. The present study provides a deeper insight into distinct molecular mechanisms of the three bestrophinopathies facilitating functional categorization of the more than 300 known BEST1 mutations that result into the distinct retinal phenotypes.

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Long-Term Macular Changes in the First Proband of Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC) Due to a Newly Identified Mutation inBEST1

Cited by 17 publications

References 14 publications

Bestrophin 1 and retinal disease

Bestrophin 1 and retinal disease

Mislocalisation of BEST1 in iPSC-derived retinal pigment epithelial cells from a family with autosomal dominant vitreoretinochoroidopathy (ADVIRC)

Mutation-Dependent Pathomechanisms Determine the Phenotype in the Bestrophinopathies

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