Novel ABCA4 mutation leads to loss of a conserved C-terminal motif: implications for predicting pathogenicity based on genetic testing
Novel ABCA4 mutation leads to loss of a conserved C-terminal motif: implications for predicting pathogenicity based on genetic testing
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新型 ABCA4 突变导致保守 C 末端基序丢失：对基于基因检测预测致病性的影响
DOI：
10.5301/ejo.5001019
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发表时间：
2018
影响因子：
1.7
通讯作者：
E. Biswas
中科院分区：
文献类型：
--
作者：
Nutsuchar Wangtiraumnuay;J. Capasso;Mai Tsukikawa;A. Levin;E. Biswas
目的：ABCA 4基因突变导致广泛的严重视网膜变性，包括Stargardt黄斑营养不良、眼底黄斑、常染色体隐性视网膜色素变性和视锥-视杆细胞营养不良。除了检测特征明确的突变外，基因检测还经常产生意义不明的新变异。本报告的目的是描述一种方法，以帮助评估未知意义的遗传变异。病例报告：我们报告一个11岁的女孩Stargardt病窝藏新的复合杂合缺失ABCA 4（c.850_857delATTCAAGA和c.6184_6187delGTCT）。这些变体的致病性在其他方面是未知的。两种缺失均引入提前终止密码子并定位在ABCA 4的开放阅读框内。c.850_857delATTCAAGA发生在基因的早期，并导致只有317个氨基酸的显着截短的蛋白质。c.6184_6187delGTCT定位于ORF的3'末端，并导致ABCA 4的2，273个氨基酸中的最后161个氨基酸的去除，包括VFVNFA基序，其已显示在ABCA 4蛋白功能中是关键的。基于同源性的蛋白质建模的ABCA 4窝藏这种缺失表明显着的蛋白质结构和功能的改变。结论：我们的分析使我们能够将ABCA 4中的新变体分类为明显的功能丧失突变，因此是致病性变体。在未知意义的变体的情况下，使用计算机工具评估基因突变的蛋白质结构-功能后果可能有助于预测致病性不确定的变体的临床重要性。
Purpose: Mutations in the ABCA4 gene result in a broad spectrum of severe retinal degeneration, including Stargardt macular dystrophy, fundus flavimaculatus, autosomal recessive retinitis pigmentosa, and cone-rod dystrophy. In addition to the detection of well-characterized mutations, genetic testing frequently yields novel variants of unknown significance. The purpose of this report is to describe an approach to aid in the assessment of genetic variants of unknown significance. Case report: We report an 11-year-old girl with Stargardt disease harboring novel compound heterozygous deletions of ABCA4 (c.850_857delATTCAAGA and c.6184_6187delGTCT). The pathogenicity of these variants was otherwise unknown. Both deletions introduce premature stop codons and are localized within the open reading frame of ABCA4. The c.850_857delATTCAAGA occurs early in the gene and leads to a significantly truncated protein of only 317 amino acids. The c.6184_6187delGTCT, is localized to the 3’ terminus of the ORF and results in removal of the last 161 out of 2,273 amino acids of ABCA4, including the VFVNFA motif, which has been shown to be critical in ABCA4 protein function. Homology-based protein modeling of ABCA4 harboring this deletion suggests significant alterations in the protein structure and function. Conclusions: Our analyses allowed us to classify novel variants in ABCA4 as being clearly loss-of-function mutations, and thus pathogenic variants. In cases of variants of unknown significance, appraising the protein structure-function consequences of genetic mutations using in silico tools may help to predict the clinical importance of variants of uncertain pathogenicity.