Biallelic Mutation of BEST1 Causes a Distinct Retinopathy in Humans

Abstract

We describe a distinct retinal disorder, autosomal-recessive bestrophinopathy (ARB), that is consequent upon biallelic mutation in BEST1 and is associated with central visual loss, a characteristic retinopathy, an absent electro-oculogram light rise, and a reduced electroretinogram. Heterozygous mutations in BEST1 have previously been found to cause the two dominantly inherited disorders, Best macular dystrophy and autosomal-dominant vitreoretinochoroidopathy. The transmembrane protein bestrophin-1, encoded by BEST1, is located at the basolateral membrane of the retinal pigment epithelium in which it probably functions as a Cl(-) channel. We sequenced BEST1 in five families, identifying DNA variants in each of ten alleles. These encoded six different missense variants and one nonsense variant. The alleles segregated appropriately for a recessive disorder in each family. No clinical or electrophysiological abnormalities were identified in any heterozygotes. We conducted whole-cell patch-clamping of HEK293 cells transfected with bestrophin-1 to measure the Cl(-) current. Two ARB missense isoforms severely reduced channel activity. However, unlike two other alleles previously associated with Best disease, cotransfection with wild-type bestrophin-1 did not impair the formation of active wild-type bestrophin-1 channels, consistent with the recessive nature of the condition. We propose that ARB is the null phenotype of bestrophin-1 in humans.

Frequency, Genotype, and Clinical Spectrum of Best Vitelliform Macular Dystrophy: Data From a National Center in Denmark

“…None of the patients had angle closure glaucoma which may be associated with Best disease or ARB. 5,17 The youngest individual presenting with subtle retinal structural alterations due to Best disease was four years of age, described by us previously. 16 Fundus autofluorescence demonstrated hyperautofluorescence of accumulated material on Bruch´s membrane and of the precipitate-like alterations at the level of the photoreceptor outer segments that were found to be associated with subretinal fluid (Supplemental material at AJO.com or Supplemental Figs.…”

“…Autosomal recessive BEST1 mutations are usually associated with more severe retinal dystrophies, such as autosomal recessive bestrophinopathy (ARB) [1][2][3][4][5] and retinitis pigmentosa. 6 Best disease is considered a rare genetic disease, but the prevalence in still unknown.…”

Retinal structure in young patients aged 10 years or less with Best vitelliform macular dystrophy

“…Mutations in the BEST1 gene can cause a variety of ocular phenotypes ranging from isolated vitelliform macular dystrophy to widespread retinal dystrophy as in autosomal recessive bestrophinopathy and further to widespread ocular manifestations as in autosomal dominant vitreoretinochoroidopathy [1][2][3][4][5]. Among these, the most common manifestation is the classical Best vitelliform macular dystrophy or Best disease, characterized by an autosomal dominant inheritance, variable penetrance and expressivity, mostly reduced electro-oculogram and vitelliform alterations in the macula.…”

Normal Electrooculography in Best Disease and Autosomal Recessive Bestrophinopathy

“…The clinical spectrum of disorders include (i) diseases predominantly affecting the macula -Best disease (BD) and Adult Vitelliform Macular Dystrophy (AVMD); (ii) generalised retinal involvement -Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC) and Retinitis Pigmentosa (RP); and (iii) diseases with retinal and anterior segment involvement -autosomal recessive Bestrophinopathy (ARB) and Microcornea, Rod-cone dystrophy, Cataract and posterior Staphyloma (MRCS). [1][2][3][4][5][6][7] In addition to the phenotypic heterogeneity some of the bestrophinopathies display significant variation in penetrance of the clinical phenotype. 8 However, one endophenotype, the absent or reduced electrooculogram (EOG) light rise, is reported to be almost fully penetrant.…”