A Novel BEST1 Mutation in Autosomal Recessive Bestrophinopathy
A Novel BEST1 Mutation in Autosomal Recessive Bestrophinopathy
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DOI：
10.1167/iovs.15-18168
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发表时间：
2015-12-01
影响因子：
4.4
通讯作者：
Kim, Eung Kweon
中科院分区：
文献类型：
--
作者：
Lee, Christopher Seungkyu;Jun, Ikhyun;Kim, Eung Kweon
目的.目的描述一种新发现的常染色体隐性遗传性雌激素病（ARB）突变体的临床特征，并证实其相关的生理功能缺陷。来自一个家族的两名ARB患者接受了全面的眼科检查，包括散瞳眼底检查、眼底照相、荧光素血管造影、眼底自发荧光成像、光谱域光学相干断层扫描（OCT）、视网膜电图（ERG）和眼电图（EOG）。随后，通过直接桑格测序进行雌激素样肽-1（BEST 1）突变的遗传分析。通过体外实验确定BEST 1的ARB相关突变对细胞定位的影响。进行全细胞膜片钳以测量转染的HEK 293 T细胞中野生型BEST 1和鉴定的BEST 1突变体的氯离子电导。两个相关的患者（66岁的哥哥和52岁的妹妹）表现为视力下降和后极部的双侧对称性视网膜下超自发荧光物质沉积。光谱域OCT显示黄斑变薄伴黄斑下积液。该女性患者伴随左眼视网膜分支静脉阻塞相关黄斑水肿，玻璃体内注射贝伐单抗后反应良好。遗传分析表明，这两名患者是一个新的（Leu 40 Pro）和一个先前确定的（Ala 195 Val）BEST 1变异的复合杂合子。HEK 293 T细胞转染与确定BEST 1突变体显示出显着小电流相比，野生型基因转染，而细胞共转染突变体和野生型BEST 1显示出良好的氯离子电导。BEST 1在突变体中的细胞定位在质膜上。我们已经确定并描述了一个新的BEST 1突变引起ARB的表型和体外功能方面。临床疑似ARB病例需要进行基因确认以确诊。
PURPOSE. To describe the clinical characteristics associated with a newly identified mutant of autosomal recessive bestrophinopathy (ARB) and confirm the associated physiological functional defects.METHODS. Two patients with ARB from one family underwent a full ophthalmic examination, including dilated fundus examination, fundus photography, fluorescein angiography, fundus autofluorescence imaging, spectral-domain optical coherence tomography (OCT), electroretinography (ERG), and electrooculography (EOG). Subsequently, genetic analysis for bestrophin-1 (BEST1) mutations was conducted through direct Sanger sequencing. The effect of ARB-associated mutations of BEST1 on the cellular localization was determined by in vitro experiments. Whole-cell patch clamping was conducted to measure the chloride conductance of wild-type BEST1 and the identified BEST1 mutants in transfected HEK293T cells.RESULTS. Two related patients (66-year-old brother and 52-year-old sister) presented with reduced visual acuity and bilateral symmetrical subretinal deposits of hyperautofluorescent materials in the posterior pole. Spectral-domain OCT showed macular thinning with submacular fluid. The female patient had a concomitant macular edema associated with branched retinal vein occlusion in the left eye, which responded well to intravitreal bevacizumab injections. Genetic analysis demonstrated that both patients were compound heterozygous for one novel (Leu40Pro) and one previously identified (Ala195Val) BEST1 variant. HEK293T cells transfected with the identified BEST1 mutant showed significantly small currents compared to those transfected with the wild-type gene, whereas cells cotransfected with mutant and wild-type BEST1 showed good chloride conductance. Cellular localization of BEST1 was well conserved to the plasma membrane in the mutants.CONCLUSIONS. We have identified and described the phenotype and in vitro functional aspects of a new BEST1 mutation causing ARB. Clinically suspected ARB cases warrant genetic confirmation to confirm the diagnosis.