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      Retinitis pigmentosa associated with a mutation in BEST1


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          There is only one prior report associating mutations in BEST1 with a diagnosis of retinitis pigmentosa (RP). The imaging studies presented in that report were more atypical of RP and shared features of autosomal recessive bestrophinopathy and autosomal dominant vitreoretinochoroidopathy. Here, we present a patient with a clinical phenotype consistent with classic features of RP.


          The patient in this report was diagnosed with simplex RP based on clinically-evident bone spicules with characteristic ERG and EOG findings. The patient had associated massive cystoid macular edema which resolved following a short course of oral acetazolamide. Genetic testing revealed that the patient carries a novel heterozygous deletion mutation in BEST1 which is not carried by either parent. While this suggests BEST1 is causative, the patient also inherited heterozygous copies of several mutations in other genes known to cause recessive retinal degenerative disease.

          Conclusions and Importance

          How some mutations in BEST1 associate with peripheral retinal degeneration phenotypes, while others manifest as macular degeneration phenotypes is currently unknown. We speculate that RP due to BEST1 mutation requires mutations in other modifier genes.

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          Most cited references10

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          Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC).

          To investigate the genetic basis of autosomal dominant vitreoretinochoroidopathy (ADVIRC), a rare, inherited retinal dystrophy that may be associated with defects of ocular development, including nanophthalmos. A combination of linkage analysis and DNA sequencing in five families was used to identify disease-causing mutations in VMD2. The effect of these mutations on splicing was assessed using a minigene system. Three pathogenic sequence alterations in VMD2 were identified in five families with nanophthalmos associated with ADVIRC. All sequences showed simultaneous missense substitutions and exon skipping. VMD2 encodes bestrophin, a transmembrane protein located at the basolateral membrane of the RPE, that is also mutated in Best macular dystrophy. We support that each heterozygous affected individual produces three bestrophin isoforms consisting of the wild type and two abnormal forms: one containing a missense substitution and the other an in-frame deletion. The data showed that VMD2 mutations caused defects of ocular patterning, supporting the hypothesized role for the RPE, and specifically VMD2, in the normal growth and development of the eye.
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            Structure and selectivity in bestrophin ion channels.

            Human bestrophin-1 (hBest1) is a calcium-activated chloride channel from the retinal pigment epithelium, where mutations are associated with vitelliform macular degeneration, or Best disease. We describe the structure of a bacterial homolog (KpBest) of hBest1 and functional characterizations of both channels. KpBest is a pentamer that forms a five-helix transmembrane pore, closed by three rings of conserved hydrophobic residues, and has a cytoplasmic cavern with a restricted exit. From electrophysiological analysis of structure-inspired mutations in KpBest and hBest1, we find a sensitive control of ion selectivity in the bestrophins, including reversal of anion/cation selectivity, and dramatic activation by mutations at the cytoplasmic exit. A homology model of hBest1 shows the locations of disease-causing mutations and suggests possible roles in regulation.
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              Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration.

              Recently, the VMD2 gene has been identified as the causative gene in juvenile-onset vitelliform macular dystrophy (Best disease), a central retinopathy primarily characterised by an impaired function of the retinal pigment epithelium. In this study we have further characterised the spectrum of VMD2 mutations in a series of 41 unrelated Best disease patients. Furthermore we expanded our analysis to include 32 unrelated patients with adult vitelliform macular dystrophy (AVMD) and 200 patients with age-related macular degeneration (AMD). Both AVMD and AMD share some phenotypic features with Best disease such as abnormal subretinal accumulation of lipofuscin material, progressive geographic atrophy and choroidal neovascularisation, and may be the consequence of a common pathogenic mechanism. In total, we have identified 23 distinct disease-associated mutations in Best disease and four different mutations in AVMD. Two of the mutations found in the AVMD patients were also seen in Best disease suggesting a considerable overlap in the aetiology of these two disorders. There were no mutations found in the AMD group. In addition, four frequent intragenic polymorphisms did not reveal allelic association of the VMD2 locus with AMD. These data exclude a direct role of VMD2 in the predisposition to AMD.

                Author and article information

                Am J Ophthalmol Case Rep
                Am J Ophthalmol Case Rep
                American Journal of Ophthalmology Case Reports
                30 March 2016
                July 2016
                30 March 2016
                : 2
                : 11-17
                [a ]Department of Ophthalmology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, United States
                [b ]CEI Diagnostic Laboratory, Casey Eye Institute, 3375 SW Terwilliger Blvd, Portland, OR, 97239, United States
                [c ]Department of Ophthalmology, Rigshospitalet, Blegdamsvej 9, 2100, København Ø, Denmark
                Author notes
                © 2016 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                : 22 December 2015
                : 18 March 2016
                : 26 March 2016

                retinitis pigmentosa,best1,genetics,bestrophinopathy
                retinitis pigmentosa, best1, genetics, bestrophinopathy


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