Nonsense-Mediated Decay as the Molecular Cause for Autosomal Recessive Bestrophinopathy in Two Unrelated Families

Pomares, Esther; Burés-Jelstrup, Anniken; Ruiz-Nogales, Sheila; Corcóstegui, Borja; Gonzàlez‐Duarte, Roser; Navarro, Rafael

doi:10.1167/iovs.11-7964

Cited by 34 publications

(34 citation statements)

References 16 publications

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“…This was a higher number than expected, as although BEST1 mutations are associated with varied expression of the fundus phenotype, it is considered a rarity that the EOG light rise remains unaffected, with only a few individual cases reported. 3,[13][14][15][19][20][21][22][23][24] The present findings, when combined with published data, demonstrate that of the 269 unique BEST1 mutations thus far collated, at least 3.3% have now been associated with a greater than expected EOG amplitude (Table 1). 25 In collecting these data we are able to highlight two potential reasons whereby erroneous conclusions may be made when interpreting the results of either electrophysiological or genetic testing.…”

Section: Discussionsupporting

confidence: 66%

“…The same mechanism may also be proposed for the recessive c.1100+1G>A allele, suggesting that aberrant spicing does affect all transcripts. 24 Interestingly, all the mutations that have been associated with a normal EOG have also been described in individuals with a poor or absent light rise on EOG. This variability has been observed in members of the same family, again suggesting the influence of genetic or environmental modifiers.…”

Section: Discussionmentioning

confidence: 99%

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Normal Electrooculography in Best Disease and Autosomal Recessive Bestrophinopathy

Khan

Islam

Holder

et al. 2018

Retina

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SUMMARY STATEMENTThe Bestrophinopathies are a group of inherited eye disorders that arise from either dominant or recessive mutations in the BEST1 gene. Electrooculography is invaluable in the diagnosis of Best disease (BD) and autosomal recessive bestrophinopathy (ARB), as a reduced Arden ratio is a highly penetrant feature of disease. We demonstrate that EOG phenotype in BD and ARB is more variable than currently appreciated. Conclusions:The current work provides significant clinical evidence that the EOG phenotype in BD and ARB is more variable than currently appreciated. As a normal EOG may occur in the presence of a classical fundus appearance, the consequences of BEST1 mutation may be independently expressed, possibly mediated via differential effects on intracellular calcium homeostasis.4

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Normal Electrooculography in Best Disease and Autosomal Recessive Bestrophinopathy

Khan

Islam

Holder

et al. 2018

Retina

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“…2,[6][7][8][9][10][11][12][13] Other associated clinical features of ARB include hyperopia, a shallow anterior chamber, and increased incidence of angle-closure glaucoma. 7,9,12 Electrophysiology tests tend to demonstrate normal or abnormal eletroretinogram (ERG) with absent light rise in electrooculogram (EOG). Although interest in ARB has been increasing recently, much remains to be discovered about the spectrum of symptoms and clinical variability of ARB phenotypes.…”

Section: Resultsmentioning

confidence: 99%

“…[8][9][10][11][12][13][24][25][26][27][28][29] An important clinical component of ARB is its autosomal recessive nature with a BEST1-null phenotype, which makes it a potentially attractive candidate for gene replacement therapy. 12 Unlike ARB, most other diseases ascribed to BEST1 mutations are autosomal dominantly inherited.…”

Section: Discussionmentioning

confidence: 99%

A NovelBEST1Mutation in Autosomal Recessive Bestrophinopathy

Lee

Jun

Choi

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Lee CS, Jun I, Choi S, et al. A novel BEST1 mutation in autosomal recessive bestrophinopathy. Invest Ophthalmol Vis Sci. 2015;56:8141-8150. DOI:10.1167/iovs.15-18168 PURPOSE. To describe the clinical characteristics associated with a newly identified mutant of autosomal recessive bestrophinopathy (ARB) and confirm the associated physiological functional defects.METHODS. Two patients with ARB from one family underwent a full ophthalmic examination, including dilated fundus examination, fundus photography, fluorescein angiography, fundus autofluorescence imaging, spectral-domain optical coherence tomography (OCT), electroretinography (ERG), and electrooculography (EOG). Subsequently, genetic analysis for bestrophin-1 (BEST1) mutations was conducted through direct Sanger sequencing. The effect of ARB-associated mutations of BEST1 on the cellular localization was determined by in vitro experiments. Whole-cell patch clamping was conducted to measure the chloride conductance of wild-type BEST1 and the identified BEST1 mutants in transfected HEK293T cells. RESULTS.Two related patients (66-year-old brother and 52-year-old sister) presented with reduced visual acuity and bilateral symmetrical subretinal deposits of hyperautofluorescent materials in the posterior pole. Spectral-domain OCT showed macular thinning with submacular fluid. The female patient had a concomitant macular edema associated with branched retinal vein occlusion in the left eye, which responded well to intravitreal bevacizumab injections. Genetic analysis demonstrated that both patients were compound heterozygous for one novel (Leu40Pro) and one previously identified (Ala195Val) BEST1 variant. HEK293T cells transfected with the identified BEST1 mutant showed significantly small currents compared to those transfected with the wild-type gene, whereas cells cotransfected with mutant and wild-type BEST1 showed good chloride conductance. Cellular localization of BEST1 was well conserved to the plasma membrane in the mutants.CONCLUSIONS. We have identified and described the phenotype and in vitro functional aspects of a new BEST1 mutation causing ARB. Clinically suspected ARB cases warrant genetic confirmation to confirm the diagnosis.

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“…The novel mutation I366fsX18 is similar to previously reported recessive, truncation mutations associated with ARB. 3,[47][48][49] 3. In the presented family, these mutations exhibit a clear mode of autosomal recessive inheritance (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Johnson

Bachman

Gilles

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Johnson AA, Bachman LA, Gilles BJ, et al. Autosomal recessive bestrophinopathy is not associated with the loss of bestrophin-1 anion channel function in a patient with a novel BEST1 mutation. Invest Ophthalmol Vis Sci. 2015;56:4619-4630. DOI:10.1167/iovs.15-16910 PURPOSE. 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 of the mutations R141H (CGC > CAC) and I366fsX18 (c.1098_1100þ7del), identified in a patient in our practice, on Best1 trafficking, oligomerization, and channel activity. METHODS. Currents of ClÀ were assessed in transfected HEK293 cells using whole-cell patch clamp. Best1 localization was assessed by confocal microscopy in differentiated, humaninduced pluripotent stem cell-derived RPE (iPSC-RPE) cells following expression of mutants via adenovirus-mediated gene transfer. Oligomerization was evaluated by coimmunoprecipitation in iPSC-RPE and MDCK cells. À currents, this indicates that ARB in this patient is not caused by a loss of channel activity. Moreover, Best1 I366fsX18 differs from Best1 in that it lacks most of the cytosolic C-terminal domain, suggesting that the loss of this region contributes significantly to the pathogenesis of ARB in this patient. RESULTS. Compared to

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Nonsense-Mediated Decay as the Molecular Cause for Autosomal Recessive Bestrophinopathy in Two Unrelated Families

Cited by 34 publications

References 16 publications

Normal Electrooculography in Best Disease and Autosomal Recessive Bestrophinopathy

Normal Electrooculography in Best Disease and Autosomal Recessive Bestrophinopathy

A NovelBEST1Mutation in Autosomal Recessive Bestrophinopathy

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

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