Assessment of mutations in the best macular dystrophy (VMD2) gene in patients with adult-onset foveomacular vitelliform dystrophy, age-related maculopathy, and bull’s-eye maculopathy

doi:10.1016/S0161-6420(01)00777-1

Ophthalmology

Volume 108, Issue 11, November 2001, Pages 2060-2067

Presented as a poster at the American Academy of Ophthalmology annual meeting, Orlando, Florida, October 1999.

https://doi.org/10.1016/S0161-6420(01)00777-1 Get rights and content

Abstract

Purpose

To study the presence of Best macular dystrophy (VMD2) gene mutations in patients diagnosed with maculopathies other than classic Best disease and to describe the clinical characteristics of these subjects.

Design

Case-comparison study of phenotype-genotype correlations.

Methods

Patients with either age-related maculopathy (ARM; n = 259) or maculopathies other than classic Best disease (n = 28) were screened for mutations in the Best gene (VMD2; OMIM 153700). These cases were compared with ethnically similar subjects in the same age range without maculopathy (n = 196). All patients underwent a complete dilated ocular examination, and all affected individuals underwent fundus photography. Phenotype-genotype comparisons were made.

Main outcome measures

Presence of mutations in the Best gene (VMD2; OMIM 153700) and the clinical phenotype.

Results

Three of 259 patients (1%) with ARM and 2 of 28 patients (7%) with other maculopathies including 1 of 3 patients with adult-onset foveomacular vitelliform dystrophy and 1 of 5 patients with a bull’s eye maculopathy, but none of the controls, were found to possess amino acid-changing variants in the VMD2 gene. These included a man with confluent drusen and retinal pigment epithelial detachments (variant in exon 6; T216I), a man with geographic atrophy and numerous soft drusen (variant in exon 10; L567F), a woman with drusen and retinal pigment epithelial alterations (variant in exon 10; L567F), a woman with drusen and retinal pigment epithelial alterations resembling bull’s-eye maculopathy (variant in exon 4; E119Q), and a woman diagnosed with adult-onset foveomacular vitelliform dystrophy (variant in exon 4; A146K).

Conclusions

Novel mutations in the VMD2 gene were found in patients diagnosed with maculopathies other than classic Best disease. Some cases diagnosed as adult-onset vitelliform foveomacular dystrophy may represent a variant of Best disease with delayed onset. The VMD2 gene does not play a major role in the development of ARM.

Section snippets

Materials and methods

The Family Macular Degeneration Study is a National Institutes of Health-supported, Massachusetts Eye and Ear Infirmary Human Subject Committee-approved study being performed to determine the genetic basis of macular degeneration. As part of this study, patients are asked questions about their family members, and a complete pedigree is constructed. All participants consent to a thorough ocular evaluation with fundus photography, which may also include diagnostic testing when appropriate

Patient 1

A 72-year-old male noted mild gradual visual deterioration over a 13-year period. The patient reported no family history of eye problems or visual loss. In February 1995, his visual acuity was recorded as 20/25 in each eye. His anterior segment examination results were within normal limits. Funduscopic examination revealed large confluent drusen and hypopigmentation and clumping of RPE in both eyes. There was no evidence of basal laminar drusen in either eye. Fluorescein angiography

Discussion

Four unique variants were detected in the VMD2 (Best) gene in 5 patients with maculopathies: 3 of 259 subjects (approximately 1%) with age-related maculopathy, and 2 of 28 other subjects (approximately 7%) with maculopathies not diagnosed as classic Best disease. These two latter cases with genetic variants in VMD2 included one of three subjects with adult-onset foveomacular vitelliform maculopathy and one of five subjects with bull’s-eye maculopathy. It is interesting to note that three of

Acknowledgements

The authors thank the patients and the referring physicians, without whose cooperation this work would not have been possible.

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The protein, human Best1 (hBest1), encoded by this gene, is an integral membrane protein found primarily in the RPE, which functions as an anion channel (332–334). Mutations in the BEST1 gene have been uncovered as the cause of several other ocular diseases, including adult-onset macular dystrophy and bull’s eye maculopathy (335). In addition to a nonfunctional hBest1 protein, disruption of processes that regulate hBest1 function can also lead to retinopathies.
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Thirty-seven BEST1 mutations were detected in 53 vitelliform macular dystrophy patients in our study. The mutation detection rate was 40% (53/134) in total, 45% in BVMD patients, 82% in ARB or ARB-like patients, and 0% in AVMD patients, which is in accordance with previous reports showing that the mutation rate was around 50%-86% in BVMD patients,13,29,31,39,42 100% in ARB patients,2,36 and 0%-33% in AVMD patients.29,43 The majority of BEST1 mutations (32/37) in our patients were missense mutations, which was also consistent with previous studies.1,12
To provide the clinical and genetic characteristics of a large cohort of Chinese patients with vitelliform macular dystrophies.
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In total, 87 BVMD, 30 AVMD, and 17 ARB patients were enrolled in this study. Genetic analysis identified 37 BEST1 mutations in 53 patients with BVMD and ARB. Of these, 5 variants (c.254A>C, c.291C>G, c.722C>G, c.848_850del, c.1740-2A>C) were novel. The variant c.898G>A was a hotspot mutation, which was identified in 13 patients with BVMD and 1 patient with ARB. There were significant differences of ocular biometric parameters among patients with homozygous or compound heterozygous mutations, heterozygous mutations, and those without mutations of BEST1. Homozygous or compound heterozygous patients had shortest axial length (AL), shallowest anterior chamber depth (ACD), and highest intraocular pressure (IOP); patients without mutations had longest AL, deepest ACD, and lowest IOP; and heterozygous patients were in between. Moreover, 7 patients harboring heterozygous mutations in BEST1 and 3 patients without BEST1 mutations showed similar clinical appearance to ARB in our cohort.
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^☆: Supported in part by the National Eye Institute, Bethesda, Maryland (grant nos.: EY11309 [JMS] and EY11600 [PSB]; Research to Prevent Blindness, Inc., New York, New York; an RPB Lew R. Wasserman Merit Award (JMS); an RPB career development award (PSB and RA); the Lions Eye Research Fund, Inc., Northboro, Mass., an unrestricted grant to Moran Eye Center; and The Ruth and Milton Steinbach Fund, New York, NY.

¹: The authors have no proprietary interest in the products or devices mentioned herein.

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Assessment of mutations in the best macular dystrophy (VMD2) gene in patients with adult-onset foveomacular vitelliform dystrophy, age-related maculopathy, and bull’s-eye maculopathy1☆,

Abstract

Purpose

Design

Methods

Main outcome measures

Results

Conclusions

Section snippets

Materials and methods

Patient 1

Discussion

Acknowledgements

Am J Ophthalmol

Am J Ophthalmol

Ophthalmology

Am J Ophthalmol

Am J Ophthalmol

Am J Hum Genet

Surv Ophthalmol

Am J Ophthalmol

Best’s vitelliform dystrophy

Ophthalmic Pediatr Genet

Best’s vitelliform macular dystrophy

Acta Ophthalmol Suppl

A clinicopathologic study of a peculiar foveomacular dystrophy

Trans Am Ophthalmol Soc

Genetic risk of age-related maculopathy. Population-based familial aggregation study

Arch Ophthalmol

Heredity and age-related macular degeneration. Observations in monozygotic twins

Arch Ophthalmol

Sibling correlations and segregation analysis of age-related maculopathythe Beaver Dam Eye Study

Genet Epidemiol

Exclusion of TIMP3 as a candidate locus in age-related macular degeneration

Invest Ophthalmol Vis Sci

Assessment of mutations in the best macular dystrophy (VMD2) gene in patients with adult-onset foveomacular vitelliform dystrophy, age-related maculopathy, and bull’s-eye maculopathy¹☆,