Abstract
Adult-onset vitelliform macular dystrophy (AVMD) is a common and benign macular degeneration which can be caused by BEST1 mutation. Here, we investigated the clinical characteristics associated with a newly identified BEST1 mutation, p.Ile38Ser and confirmed the associated physiological functional defects. The 51-year-old patient presented bilateral small subretinal yellow deposits. Consistent with AVMD, the corresponding lesions showed hyperautofluorescence, late staining in fluorescein angiography, and subretinal hyper-reflective materials in spectral-domain optical coherence tomography. Genetic analysis demonstrated that the patient presented with a heterozygous p.Ile38Ser BEST1 mutation. Surface biotinylation and patch clamp experiments were performed in transfected HEK293T cells. Although, the identified BEST1 mutant maintains normal membrane expression, p.Ile38Ser mutant showed significantly smaller currents than wild type (WT). However, it showed larger currents than other BEST1 mutants, p.Trp93Cys, causing autosomal dominant best vitelliform macular dystrophy (BVMD), and p.Ala195Val, causing autosomal recessive bestrophinopathy (ARB). The cells expressing both WT and each BEST1 mutant showed that the functional defect of p.Ile38ser was milder than that of p.Trp93Cys, whereas combination of p.Ala195Val with WT showed good current. We identified and described the phenotype and in vitro functions of a novel BEST1 mutation causing AVMD. AVMD induced by p.Ile38Ser BEST1 mutation is a mild form of BVMD.
Highlights
Adult-onset vitelliform macular dystrophy (AVMD) is one of the most common forms of macular degeneration[7]
Several nonsynonymous variants were detected (Supplementary Table S1), but all of them are reported as single nucleotide polymorphism (SNP), of which minor allele frequencies are greater than 1%; they are not likely to be disease-causing
The BEST1 p.Ile38Ser mutation has not been previously reported in patients with BEST1-associated disease, or in SNP databases such as dbSNP or Exome Aggregation Consortium (ExAC) (Table 1)
Summary
AVMD is one of the most common forms of macular degeneration[7]. The authors screened for BEST1 mutation in patients with age-related macular degeneration (AMD) and other maculopathies and concluded that BEST1 mutations could cause various disease phenotypes. Four additional BEST1 mutations, including p.Thr6Pro, p.Arg47His, p.Ala243Val, and p.Asp312Asn, were identified in patients with AVMD11. No further mutations in BEST1 have been identified by genetic screening of patients with AVMD15–19, late onset best macular dystrophy with BEST1 mutations has been investigated[20]. Because of similar clinical characteristics, AVMD induced by BEST1 mutations is considered a late-onset and mild form of BVMD2, 3, 7, there is no case report or no combined experimental evidence. No study has investigated the direct association between BEST1 mutation and AVMD pathophysiology. We present an AVMD case presenting with a novel BEST1 mutation, p.Ile38Ser, and propose that BEST1 mutation is the causative factor of AVMD based on molecular and electrophysiological in vitro experiments
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