Clinical, Genetics, and Bioinformatic Characterization of Mutations Affecting an Essential Region of PLS3 in Patients with BMND18.
Clinical, Genetics, and Bioinformatic Characterization of Mutations Affecting an Essential Region of PLS3 in Patients with BMND18.
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影响 BMND18 患者 PLS3 重要区域的突变的临床、遗传学和生物信息学特征
DOI：
10.1155/2018/8953217
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发表时间：
2018
影响因子：
2.8
通讯作者：
Xiao F
中科院分区：
文献类型：
--
作者：
Chen T;Wu H;Zhang C;Feng J;Chen L;Xie R;Wang F;Chen X;Zhou H;Sun H;Xiao F
骨矿物质密度定量性状基因座18（BMND 18，OMIM #300910）是由PLS 3基因中的功能缺失突变引起的早发性成骨细胞（OI）类型，所述PLS 3基因编码在整个细胞骨架中形成肌动蛋白束的关键蛋白质plastin-3。在这里，我们报告了一个患者的PLS 3突变引起的BMND 18和评估所有报告的致病突变的生物信息学分析。 进行靶向基因测序以找到我们患者的致病突变。生物信息学分析主要包括同源性建模和分子动力学模拟，以探索以前报道的突变对plastin-3的影响。 基因测序结果显示，在PLS 3基因的高度保守区域（第240 -266位残基）（LOOP-1）存在一个新的无义突变（c.745G > T，p.E249X）。对先前报道的突变的进一步生物信息学分析显示，预测LOOP-1物理连接ABD 1片段的钙调蛋白同源1（CH 1）和CH 2结构域，并且在空间上位于ABD 1和ABD 2的界面内。它对plastin-3的构象转变和肌动蛋白结合功能至关重要。 该报告鉴定了一种截短PLS 3基因的新突变。此外，生物信息学分析的PLS 3基因的突变导致我们发现一个关键的LOOP-1区域的plastin-3的突变，可能是有害的plastin-3的整体构象，从而影响其结合肌动蛋白丝。
Bone mineral density quantitative trait locus 18 (BMND18, OMIM #300910) is a type of early-onset osteogenesis imperfecta (OI) caused by loss-of-function mutations in the PLS3 gene, which encodes plastin-3, a key protein in the formation of actin bundles throughout the cytoskeleton. Here, we report a patient with PLS3 mutation caused BMND18 and evaluated all the reported disease-causing mutations by bioinformatic analysis. Targeted gene sequencing was performed to find the disease-causing mutation in our patient. Bioinformatic analyses mainly including homology modelling and molecular dynamics stimulation were conducted to explore the impact of the previously reported mutations on plastin-3. Gene sequencing showed a novel nonsense mutation (c.745G > T, p.E249X), which locates at a highly conserved region containing residues p.240–266 (LOOP-1) in the PLS3 gene. Further bioinformatic analyses of the previously reported mutations revealed that LOOP-1 is predicted to physically connect the calponin-homology 1 (CH1) and CH2 domains of the ABD1 fragment and spatially locates within the interface of ABD1 and ABD2. It is crucial to the conformation transition and actin-binding function of plastin-3. This report identified a novel mutation that truncates the PLS3 gene. Moreover, bioinformatic analyses of the previous reported mutations in PLS3 gene lead us to find a critical LOOP-1 region of plastin-3 mutations at which may be detrimental to the integral conformation of plastin-3 and thus affect its binding to actin filament.
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影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
--
作者：
Shinomiya H
通讯作者：
Shinomiya H
影响因子：
2
作者：
Van Dijk, F. S.;Sillence, D. O.
通讯作者：
Sillence, D. O.
肌动蛋白丝的原子模型，与fimbrin交联及其对束组件和功能的影响。
影响因子：
7.8
作者：
Volkmann, N;DeRosier, D;Matsudaira, P;Hanein, D
通讯作者：
Hanein, D
影响因子：
6.2
作者：
Fahiminiya, Somayyeh;Majewski, Jacek;Rauch, Frank
通讯作者：
Rauch, Frank