Structural and Pathogenic Impacts of ABCA4 Variants in Retinal Degenerations-An In-Silico Study.
Structural and Pathogenic Impacts of ABCA4 Variants in Retinal Degenerations-An In-Silico Study.
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DOI：
10.3390/ijms24087280
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发表时间：
2023-04-14
影响因子：
5.6
通讯作者：
Biswas-Fiss, Esther E.
中科院分区：
文献类型：
--
作者：
Cevik, Senem;Biswas, Subhasis B.;Biswas-Fiss, Esther E.
视网膜特异的三磷酸腺苷结合盒转运蛋白ABCA4负责通过去除光传导的有毒维甲酸副产物来正确地延续视觉周期。由ABCA4序列变异引起的功能障碍是常染色体隐性遗传性视网膜疾病的主要原因，包括Stargardt病、视网膜色素变性和视锥-杆状营养不良。到目前为止，已鉴定出3000多个ABCA4基因变异，其中约40%尚未被分类用于致病性评估。这项研究使用AlphaFold2蛋白建模和计算结构分析来检测30个错义ABCA4变体，以预测致病性。所有被归类为致病的变异(n=10)都被发现具有有害的结构后果。在10个良性变异中，8个在结构上是中性的，其余两个导致了轻微的结构变化。这项研究的结果为临床意义不确定的八种ABCA4变异体提供了多条计算致病性证据。总体而言，ABCA4的分析可以为了解视网膜变性的分子机制及其致病影响提供有价值的工具。
The retina-specific ATP-binding cassette transporter protein ABCA4 is responsible for properly continuing the visual cycle by removing toxic retinoid byproducts of phototransduction. Functional impairment caused by ABCA4 sequence variations is the leading cause of autosomal recessive inherited retinal disorders, including Stargardt disease, retinitis pigmentosa, and cone-rod dystrophy. To date, more than 3000 ABCA4 genetic variants have been identified, approximately 40 percent of which have not been able to be classified for pathogenicity assessments. This study examined 30 missense ABCA4 variants using AlphaFold2 protein modeling and computational structure analysis for pathogenicity prediction. All variants classified as pathogenic (n = 10) were found to have deleterious structural consequences. Eight of the ten benign variants were structurally neutral, while the remaining two resulted in mild structural changes. This study’s results provided multiple lines of computational pathogenicity evidence for eight ABCA4 variants of uncertain clinical significance. Overall, in silico analyses of ABCA4 can provide a valuable tool for understanding the molecular mechanisms of retinal degeneration and their pathogenic impact.
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影响因子：
2.9
作者：
Biswas-Fiss, EE
通讯作者：
Biswas-Fiss, EE
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
14.9
作者：
Desmet FO;Hamroun D;Lalande M;Collod-Béroud G;Claustres M;Béroud C
通讯作者：
Béroud C
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
3.9
作者：
Curtis SB;Molday LL;Garces FA;Molday RS
通讯作者：
Molday RS