BEST1: the Best Target for Gene and Cell Therapies

Yang, Tingting; Justus, Sally; Li, Yao; Tsang, Stephen H.

doi:10.1038/mt.2015.177

Cited by 41 publications

(40 citation statements)

References 30 publications

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“…We then modeled the SLC38A8 tertiary structure using a threading approach (Zhang, ; Roy et al., ; Yang et al. ; Yang and Zhang, )). The generated model matched the membrane topological predictions made in TMHMM (Fig.…”

Section: Resultsmentioning

confidence: 99%

Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia

Toral

Vélez

Boudreault

et al. 2017

Molec Gen & Gen Med

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BackgroundFoveal hypoplasia (FH) in the absence of albinism, aniridia, microphthalmia, or achromatopsia is exceedingly rare, and the molecular basis for the disorder remains unknown. FH is characterized by the absence of both the retinal foveal pit and avascular zone, but with preserved retinal architecture. SLC38A8 encodes a sodium‐coupled neutral amino acid transporter with a preference for glutamate as a substrate. SLC38A8 has been linked to FH. Here, we describe a novel mutation to SLC38A8 which causes FH, and report the novel use of OCT‐angiography to improve the precision of FH diagnosis. More so, we used computational modeling to explore possible functional effects of known SLC38A8 mutations.MethodsFundus autofluorescence, SD‐OCT, and OCT‐angiography were used to make the clinical diagnosis. Whole‐exome sequencing led to the identification of a novel disease‐causing variant in SLC38A8. Computational modeling approaches were used to visualize known SLC38A8 mutations, as well as to predict mutation effects on transporter structure and function.ResultsWe identified a novel point mutation in SLC38A8 that causes FH. A conclusive diagnosis was made using OCT‐angiography, which more clearly revealed retinal vasculature penetrating into the foveal region. Structural modeling of the channel showed the mutation was near previously published mutations, clustered on an extracellular loop. Our modeling also predicted that the mutation destabilizes the protein by altering the electrostatic potential within the channel pore.ConclusionOur results demonstrate a novel use for OCT‐angiography in confirming FH, and also uncover genotype–phenotype correlations of FH‐linked SLC38A8 mutations.

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Section: Resultsmentioning

confidence: 99%

Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia

Toral

Vélez

Boudreault

et al. 2017

Molec Gen & Gen Med

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“…33 While these trials are still in the data-gathering and laboratory phases, future therapeutic clinical trials may come as a result of this work, possibly involving gene therapy or stem cells. 28,29 These therapies will likely be somewhat individualized, depending on the specific causative mutation(s) found in a given patient, which will undoubtedly make genetic testing a critical aspect of patient care. Moreover, the knowledge of the underlying genetics of these inherited diseases has important implications for family members who may not currently have any symptoms but are at risk of developing vision loss in the future.…”

Section: Discussionmentioning

confidence: 99%

Vitelliform dystrophies: Prevalence in Olmsted County, Minnesota, United States

Dalvin

Pulido

Marmorstein

2016

Ophthalmic Genetics

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Background Vitelliform dystrophies are a group of macular degenerative diseases characterized by round yellow lesions in the macula. While often idiopathic, vitelliform dystrophies include inherited maculopathies such as Best disease and some cases of pattern dystrophy. The prevalence of vitelliform dystrophies in the United States has not been reported. This study examined the prevalence of vitelliform dystrophies in Olmsted County, Minnesota. Materials and Methods The Rochester Epidemiology Project database was used to identify all cases of vitelliform or pattern dystrophy in Olmsted County from 1/1/2000–12/31/2014. Results 27 patients had true vitelliform lesions, indicating a prevalence of 1 in 5500. Of these, 2 had genetically confirmed Best disease, and an additional 5–7 carried a diagnosis of Best disease, which chart reviews confirmed as probable cases; 18–20 patients had adult-onset vitelliform macular dystrophy. The prevalence of Best disease was 1 in 16,500 to 1 in 21,000. Adult-onset vitelliform macular dystrophy was found in 1 in 7400 to 1 in 8200. Conclusions Vitelliform dystrophies affect 1 in 5500 individuals in Olmsted County. While the values in this study provide good estimates for the prevalence of Best disease versus adult-onset vitelliform macular dystrophy, the results are limited by dependence on diagnoses made by other ophthalmologists and underutilization of genetic testing. Thus, these diseases should be thought of as at least as prevalent as reported here. As therapies for Best disease and other macular degenerative diseases are quickly becoming a reality, genetic testing should be employed as the gold standard for diagnosis of these diseases.

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“…The BEST1 mutational spectrum underlying these retinopathies varies greatly, and involves over 200 distinct mutations (Boon et al, 2009a; Pasquay et al, 2015; Yang et al, 2015). Additionally, a considerable variability in age at onset, rate of disease progression and phenotypic expression has been reported, not only between unrelated patients harboring the same mutation, but also among affected individuals within a single family (Kramer et al, 2000; Kinnick et al, 2011; Bitner et al, 2012; MacDonald et al, 2012; Boon et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Bestrophinopathy: An RPE-photoreceptor interface disease

Guziewicz

Sinha

Gómez

et al. 2017

Progress in Retinal and Eye Research

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Bestrophinopathies, one of the most common forms of inherited macular degenerations, are caused by mutations in the BEST1 gene expressed in the retinal pigment epithelium (RPE). Both human and canine BEST1-linked maculopathies are characterized by abnormal accumulation of autofluorescent material within RPE cells and bilateral macular or multifocal lesions; however, the specific mechanism leading to the formation of these lesions remains unclear. We now provide an overview of the current state of knowledge on the molecular pathology of bestrophinopathies, and explore factors promoting formation of RPE-neuroretinal separations, using the first spontaneous animal model of BEST1-associated retinopathies, canine Best (cBest). Here, we characterize the nature of the autofluorescent RPE cell inclusions and report matching spectral signatures of RPE-associated fluorophores between human and canine retinae, indicating an analogous composition of endogenous RPE deposits in Best Vitelliform Macular Dystrophy (BVMD) patients and its canine disease model. This study also exposes a range of biochemical and structural abnormalities at the RPE-photoreceptor interface related to the impaired cone-associated microvillar ensheathment and compromised insoluble interphotoreceptor matrix (IPM), the major pathological culprits responsible for weakening of the RPE-neuroretina interactions, and consequently, formation of vitelliform lesions. These salient alterations detected at the RPE apical domain in cBest as well as in BVMD- and ARB-hiPSC-RPE model systems provide novel insights into the pathological mechanism of BEST1-linked disorders that will allow for development of critical outcome measures guiding therapeutic strategies for bestrophinopathies.

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BEST1: the Best Target for Gene and Cell Therapies

Cited by 41 publications

References 30 publications

Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia

Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia

Vitelliform dystrophies: Prevalence in Olmsted County, Minnesota, United States

Bestrophinopathy: An RPE-photoreceptor interface disease

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