"Bestrophin 1"

Small Molecules Restore Bestrophin 1 Expression and Function of Both Dominant and Recessive Bestrophinopathies in Patient-Derived Retinal Pigment Epithelium. Bestrophinopathies are a group of untreatable inherited retinal dystrophies caused by mutations in the retinal pigment epithelium (RPE) Cl- channel bestrophin 1. We tested whether sodium phenylbutyrate (4PBA) could rescue the function of mutant bestrophin 1 associated with autosomal dominant and recessive disease. We then sought analogues of 4PBA with increased potency and determined the mode of action for 4PBA and a lead compound 2-naphthoxyacetic acid (2-NOAA). Lastly, we tested if 4PBA and 2-NOAA could functionally rescue bestrophin 1 function in RPE generated from induced pluripotent stem cells (iPSC-RPEs) derived from patients

Mutation spectrum of the bestrophin-1 gene in a large Chinese cohort with bestrophinopathy. Bestrophin-1 () gene is associated with a wide range of ocular phenotypes, collectively termed as bestrophinopathy. The aim of the current study was to identify the mutation spectrum of in a large cohort of Chinese patients with bestrophinopathy. Patients clinically suspected of bestrophinopathy were

Bestrophin 1 and retinal disease. 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 Ca signaling. Best1 is an integral

Genetic variations in Bestrophin-1 and associated clinical findings in two Chinese patients with juvenile-onset and adult-onset best vitelliform macular dystrophy Best vitelliform macular dystrophy (BVMD) is a hereditary retinal disease characterized by the bilateral accumulation of large egg yolk‑like lesions in the sub‑retinal and sub‑retinal pigment epithelium spaces. Macular degeneration , and 200 unrelated subjects within in the same population. The 11 exons of the bestrophin‑1 (BEST1) gene were amplified by polymerase chain reaction and directly sequenced. Both patients presented lesions in the macular area. In Patient 1, a heterozygous mutation c.903T>G (p.D301E) in exon 8 of the BEST1 gene was identified. This mutation was not present in any of the unaffected family members

Bestrophin 1 gene analysis and associated clinical findings in a Chinese patient with Best vitelliform macular dystrophy The aim of the present study was to investigate the clinical characteristics and the underlying genetic causes of Best vitelliform macular dystrophy (BVMD) in a sporadic case in a Chinese patient. A 10‑year‑old boy was diagnosed with BVMD; complete ophthalmic examinations were of 11 exons of the bestrophin 1 (BEST1) gene were amplified by polymerase chain reaction and directly sequenced. The results revealed that the patient presented with yellowish lesions in the macular area. Heterozygous mutations c.292G>A (p.Glu98Lys) in exon 4 and c.1608C>T (p.Thr536Thr) in exon 10 of the BEST1 gene were identified in this sporadic case; however, this was not identified in any of his

Distribution and Function of the Bestrophin-1 (Best1) Channel in the Brain Bestrophin-1 (Best1) is a calcium-activated anion channel identified from retinal pigment epithelium where human mutations are associated with Best's macular degeneration. Best1 is known to be expressed in a variety of tissues including the brain, and is thought to be involved in many physiological processes. This review

Restoration of mutant bestrophin-1 expression, localisation and function in a polarised epithelial cell model Autosomal recessive bestrophinopathy (ARB) is a retinopathy caused by mutations in the bestrophin-1 protein, which is thought to function as a Ca-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

Phasing and structure of bestrophin-1: a case study in the use of heavy-atom cluster compounds with multi-subunit transmembrane proteins The purification and three-dimensional crystallization of membrane proteins are commonly affected by a cumulation of pathologies that are less prevalent in their soluble counterparts. This may include severe anisotropy, poor spot shape, poor to moderate -resolution diffraction, crystal twinning, translational pseudo-symmetry and poor uptake of heavy atoms for derivatization. Such challenges must be circumvented by adaptations in the approach to crystallization and/or phasing. Here, an example of a protein that exhibited all of the above-mentioned complications is presented. Bestrophin-1 is a eukaryotic calcium-activated chloride channel, the structure

Two novel mutations in the bestrophin-1 gene and associated clinical observations in patients with best vitelliform macular dystrophy The purpose of the current study was to investigate the 11 bestrophin-1 (BEST1) exons in patients with best vitelliform macular dystrophy (BVMD), and to characterize the associated clinical features. Complete ophthalmic examinations were conducted on two families

Bestrophin 1 is indispensable for volume regulation in human retinal pigment epithelium cells In response to cell swelling, volume-regulated anion channels (VRACs) participate in a process known as regulatory volume decrease (RVD). Only recently, first insight into the molecular identity of mammalian VRACs was obtained by the discovery of the leucine-rich repeats containing 8A (LRRC8A) gene. Here , we show that bestrophin 1 (BEST1) but not LRRC8A is crucial for volume regulation in human retinal pigment epithelium (RPE) cells. Whole-cell patch-clamp recordings in RPE derived from human-induced pluripotent stem cells (hiPSC) exhibit an outwardly rectifying chloride current with characteristic functional properties of VRACs. This current is severely reduced in hiPSC-RPE cells derived from

Autosomal Recessive Bestrophinopathy Is Not Associated With the Loss of Bestrophin-1 Anion Channel Function in a Patient With a Novel BEST1 Mutation. Mutations in BEST1, encoding bestrophin-1 (Best1), cause autosomal recessive bestrophinopathy (ARB). Encoding bestrophin-1 is a pentameric anion channel localized to the basolateral plasma membrane of the RPE. Here, we characterize the effects

Role of anoctamin-1 and bestrophin-1 in spinal nerve ligation-induced neuropathic pain in rats Calcium-activated chloride channels (CaCCs) activation induces membrane depolarization by increasing chloride efflux in primary sensory neurons that can facilitate action potential generation. Previous studies suggest that CaCCs family members bestrophin-1 and anoctamin-1 are involved in inflammatory pain. However, their role in neuropathic pain is unclear. In this investigation we assessed the involvement of these CaCCs family members in rats subjected to the L5/L6 spinal nerve ligation. In addition, anoctamin-1 and bestrophin-1 mRNA and protein expression in dorsal root ganglion (DRG) and spinal cord was also determined in the presence and absence of selective inhibitors. L5/L6 spinal nerve

Transepithelial resistance in human bestrophin-1 stably transfected Madin–Darby canine kidney cells Bestrophin-1 (Best1) is a transmembrane protein, found in the basolateral plasma membrane of retinal pigmented epithelial cells. The exact structure and functions of Best1 protein are still unclear. The protein is thought to be a regulator of ion channels, or an ion channel itself: it was shown

Astrocytic BEST1 can serve as a target for functional recovery after ischemic stroke. Solid evidence from animal experiments supported the concept of peri-infarct tonic inhibition. Related drug targets have the potential to be translated for clinical stroke treatment. Recently, we reported the contribution of neuronal Bestrophin-1 (BEST1)-mediated glutamate release to acute ischemic damage

Autosomal recessive bestrophinopathy combined with neurofibromatosis type 1 in a patient. Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder that may affect multiple systems of the body. Autosomal recessive bestrophinopathy (ARB) is a rare retinal dystrophy caused by autosomal recessively mutations in bestrophin 1 (BEST1) gene. So far, we have not retrieved any case report

on excitation/inhibition balance. We have previously reported that astrocytic GABA, synthesized by monoamine oxidase B (MAOB), mediates tonic inhibition via GABA-permeable bestrophin 1 (Best1) channel in the cerebellum. However, the role of astrocytic GABA in regulating neuronal excitability, synaptic transmission, and cerebellar brain function has remained elusive. Here, we report that a reduction of tonic

BEST1 protein stability and degradation pathways differ between autosomal dominant Best disease and autosomal recessive bestrophinopathy accounting for the distinct retinal phenotypes Mutations in bestrophin-1 (BEST1) are associated with distinct retinopathies, notably three forms with autosomal dominant inheritance and one condition with an autosomal recessive mode of transmission. The molecular

Mutant Best1 Expression and Impaired Phagocytosis in an iPSC Model of Autosomal Recessive Bestrophinopathy Autosomal recessive bestrophinopathy (ARB) is caused by mutations in the gene BEST1 which encodes bestrophin 1 (Best1), an anion channel expressed in retinal pigment epithelial (RPE) cells. It has been hypothesized that ARB represents the human null phenotype for BEST1 and that this occurs

. Immunohistochemistry identified cells expressing α-smooth muscle actin, glial fibrillary acidic protein, Bestrophin-1, and F4/80, suggesting the presence of multiple cell types in PVR. Robust PVR primary cultures (C-PVR) were successfully obtained from human membranes, and these cells retained the expression of cell identity markers in culture. C-PVR cultures formed membranes and band-like structures in culture

sequencing of the known genes involved in ocular disease was performed. The functional effects of the mutation were analyzed using Polymorphism Phenotyping (PolyPhen) and Sorting Intolerant From Tolerant (SIFT). One heterozygous bestrophin 1 (BEST1) mutation c.1037C>A (p.Pro346His, p.P346H) in exon 9 and one heterozygous regulating synaptic membrane exocytosis 1 (RIMS1) mutation c.3481A>G (p.Arg1161Gly