Autosomal Recessive Bestrophinopathy

Boon, Camiel J F; Born, L. Ingeborgh van den; Visser, Linda; Keunen, Jan E.E.; Bergen, Arthur A. B.; Booij, Judith C.; Riemslag, Frans C. C.; Florijn, Ralph J.; Schooneveld, Mary J. van

doi:10.1016/j.ophtha.2012.09.057

Cited by 112 publications

(75 citation statements)

References 49 publications

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“…The second mutation can either seem benign or be associated with another bestrophinopathy. An individual with ARB has been reported with p.R141H and p.D312N (Boon et al, 2013); as discussed above for p.R141H, p.D312N can either be asymptomatic in carriers or act dominantly in individuals with Best disease (Burgess et al, 2008; Sodi et al, 2011), giving the situation where two autosomal dominant mutations occur as compound heterozygous mutations to cause an autosomal recessive disease. Similar confounding combinations with p.R141H have also been reported with p.L41P, p.Y29X, p.P233A and p.I266fsX18 (Burgess et al, 2008; Schatz et al, 2006; Wittström et al, 2011; Johnson et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…It can be asymptomatic in some heterozygous carriers (Burgess et al, 2008; Iannaccone et al, 2011; Kinnick et al, 2011; Wittström et al, 2011), whereas in others it can associated with mildly abnormal electroretinogram (ERG) and electrooculogram (EOG) results, indicating abnormal functioning of the photoreceptors and RPE, respectively (Wittström et al, 2011). Individuals with ARB who are homozygous for p.R141H have either abnormal or severely abnormal ERGs (Boon et al, 2013). In other individuals p.R141H acts dominantly and causes Best disease (Krämer et al, 2000; Lotery et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it would seem that the pathogenic mechanism not only varies from mutation to mutation, but also on what other mutation is present and as-yet-unidentified factors such as promoter strength, modifying genes and environment. Another possibility is that it is not the adult function of bestrophin-1 that is important, but what role it might have had in development (Boon et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

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Restoration of mutant bestrophin-1 expression, localisation and function in a polarised epithelial cell model

Uggenti

Briant

Streit

et al. 2016

Disease Models &Amp; Mechanisms

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Autosomal recessive bestrophinopathy (ARB) is a retinopathy caused by mutations in the bestrophin-1 protein, which is thought to function as a Ca2+-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), successfully restored the expression and localisation of all four ARB mutant bestrophin-1 proteins. Importantly, the Cl− conductance function of each of the mutant bestrophin-1 proteins was fully restored to that of wild-type bestrophin-1 by treatment of cells with 4PBA alone. The functional rescue achieved with 4PBA is significant because it suggests that this drug, which is already approved for long-term use in infants and adults, might represent a promising therapy for the treatment of ARB and other bestrophinopathies resulting from missense mutations in BEST1.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Restoration of mutant bestrophin-1 expression, localisation and function in a polarised epithelial cell model

Uggenti

Briant

Streit

et al. 2016

Disease Models &Amp; Mechanisms

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“…These are often small and fleck-like or punctate in shape, white or yellow in colour, and hyperfluoresce on fundus autofluorescence imaging. Optical coherence tomography (OCT) shows subretinal and intraretinal fluid accumulation, often at the maculae [9, 18–21]. Using higher resolution Fourier-domain OCT, Gerth et al [17] demonstrated RPE deposits and significant photoreceptor changes but preserved inner retinal layers in an 11-year-old boy with ARB, including thickened, elongated photoreceptor outer segments and detachment from the RPE.…”

Section: Discussionmentioning

confidence: 99%

“…Davidson et al [20] described two unrelated cases of ARB, both of whom had angle-closure glaucoma contributing to their visual loss. All ten patients with ARB examined by Boon et al [18] were hyperopic, and five had shallow anterior chambers and narrow angles for which they underwent prophylactic laser peripheral iridotomies. One of these patients with additional short axial lengths underwent phacoemulsification and intraocular lens implantation in an effort to deepen the anterior chamber and its angles for both eyes.…”

Section: Discussionmentioning

confidence: 99%

Autosomal recessive bestrophinopathy associated with angle-closure glaucoma

et al. 2014

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PurposeAbnormalities in the BEST1 gene have recently been recognised as causing autosomal recessive bestrophinopathy (ARB). ARB has been noted to have a variable phenotypic presentation, distinct from that of autosomal dominant Best vitelliform macular dystrophy (BVMD). Both conditions are associated with deposits in the retina, a reduced or absent electro-oculography (EOG) light rise, and the risk of developing angle-closure glaucoma. Herein, we describe the clinical and genetic characteristics of a young male diagnosed with ARB associated with angle-closure glaucoma resulting from a novel homozygous mutation in BEST1.MethodsAll research involved in this case adhered to the tenets of the Declaration of Helsinki. The proband underwent slitlamp examination, retinal autofluorescence imaging and optical coherence tomography after presenting with deteriorating vision. The findings prompted genetic testing with bi-directional DNA sequencing of coding and flanking intronic regions of BEST1. The proband’s family members were subsequently screened.ResultsA provisional diagnosis of ARB was made based on the findings of subretinal and schitic lesions on fundoscopy and retinal imaging, together with abnormal EOG and electroretinography. Genetic testing identified a novel homozygous mutation in BEST1, c.636+1 G>A. Family members were found to carry one copy of the mutation and had no clinical or electrophysiological evidence of disease. The proband was additionally diagnosed with angle-closure glaucoma requiring topical therapy, peripheral iridotomies and phacoemulsification.ConclusionsPhenotypic overlap, reduced penetrance, variable expressivity and the ongoing discovery of new forms of bestrophinopathies add to the difficulty in distinguishing these retinal diseases. All patients diagnosed with ARB or BVMD should be examined for narrow angles and glaucoma, given their frequent association with these conditions.

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