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

Krämer, Franziska; White, Karen L.; Pauleikhoff, Daniel; Gehrig, Andrea; Passmore, Lori A.; Rivera, Andrea; Rudolph, Günther; Kellner, Ulrich; Andrassi, Monika; Lorenz, Birgit; Rohrschneider, Klaus; Blankenagel, A.; Jurklies, Bernhard; Schilling, Hannah; Schütt, F.; Holz, Frank G.; Weber, Bernhard H. F.

doi:10.1038/sj.ejhg.5200447

Cited by 186 publications

(160 citation statements)

References 36 publications

(59 reference statements)

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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: 67%

“…DNA sequencing identified a BEST1 variant (p.Ala243Val) already known to cause disease BD. 3 Patient 6 had a history of poor vision from the age of 12 and was found to be hyperopic at the age of 20 years old. His left eye was amblyopic.…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

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: 67%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

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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“…Mutations in the hBest1 gene are also associated with a small fraction of cases of adult onset vitelliform macular dystrophy (Allikmets et al, 1999;Kramer et al, 2000) and autosomal dominant vitreoretinochoroidopathy (Yardley et al, 2004). The underlying mechanisms of these disorders are still unknown, mainly because the basic function of the bestrophin protein is not yet fully understood (for review see Hartzell et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

DrosophilaBestrophin-1 Chloride Current Is Dually Regulated by Calcium and Cell Volume

Chien¹,

Hartzell²

2007

J Cell Biol

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Mutations in the human bestrophin-1 (hBest1) gene are responsible for Best vitelliform macular dystrophy, however the mechanisms leading to retinal degeneration have not yet been determined because the function of the bestrophin protein is not fully understood. Bestrophins have been proposed to comprise a new family of Cl − channels that are activated by Ca 2+ . While the regulation of bestrophin currents has focused on intracellular Ca 2+ , little is known about other pathways/mechanisms that may also regulate bestrophin currents. Here we show that Cl − currents in Drosophila S2 cells, that we have previously shown are mediated by bestrophins, are dually regulated by Ca 2+ and cell volume. The bestrophin Cl − currents were activated in a dose-dependent manner by osmotic pressure differences between the internal and external solutions. The increase in the current was accompanied by cell swelling. The volume-regulated Cl − current was abolished by treating cells with each of four different RNAi constructs that reduced dBest1 expression. The volume-regulated current was rescued by transfecting with dBest1. Furthermore, cells not expressing dBest1 were severely depressed in their ability to regulate their cell volume. Volume regulation and Ca 2+ regulation can occur independently of one another: the volume-regulated current was activated in the complete absence of Ca 2+ and the Ca 2+ -activated current was activated independently of alterations in cell volume. These two pathways of bestrophin channel activation can interact; intracellular Ca 2+ potentiates the magnitude of the current activated by changes in cell volume. We conclude that in addition to being regulated by intracellular Ca 2+ , Drosophila bestrophins are also novel members of the volume-regulated anion channel (VRAC) family that are necessary for cell volume homeostasis.

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“…Unlike VMD, AVMD characteristically manifests from third to fifth decades. [13][14][15] Since its identification, over 120 diseasecausing mutations have been described in the BEST1 gene. 16 The majority of mutations are missense and located in the N-terminal of the gene.…”

mentioning

confidence: 99%

Best's macular dystrophy in Australia: phenotypic profile and identification of novel BEST1 mutations

Cohn

Turnbull

Ruddle

et al. 2010

Eye

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Purpose (1) To evaluate the spectrum of BEST1 mutations within Australian Best Disease or vitelliform macular dystrophy (VMD) pedigrees, including any novel mutations; (2) to analyse the range of clinical presentations of this cohort; (3) to determine any possible genotype-phenotype correlations and (4) to compare clinical data of patients with phenotypic VMD, both with and without a BEST1 mutation. Patients and methods Patients with suspected VMD were referred to clinical centres for ophthalmological assessment and genetic screening. When a mutation was identified in a proband, further family members were invited for clinical and genetic screening. Results We identified 42 patients with one of 13 BEST1 mutations. Seven mutations were novel. There were a further 14 probands in whom a BEST1 mutation was not identified. Median visual acuity in both VMD (mutation positive) and clinical VMD (no BEST1 mutation identified) groups reached driving standards (6/12 or better). Conclusion We did not identify any firm genotype-phenotype correlations in our Australian VMD pedigrees, in which there was a spectrum of BEST1 mutations and marked variation in clinical presentation. Genetic screening remains the gold standard for VMD diagnosis. Patients should be counselled that visual acuity might remain at or above driving standards in at least one eye even in the presence of a BEST1 mutation.

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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

Cited by 186 publications

References 36 publications

Normal Electrooculography in Best Disease and Autosomal Recessive Bestrophinopathy

Normal Electrooculography in Best Disease and Autosomal Recessive Bestrophinopathy

DrosophilaBestrophin-1 Chloride Current Is Dually Regulated by Calcium and Cell Volume

Best's macular dystrophy in Australia: phenotypic profile and identification of novel BEST1 mutations

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