In Silico and In Vivo Analysis of Amino Acid Substitutions That Cause Laminopathies.
In Silico and In Vivo Analysis of Amino Acid Substitutions That Cause Laminopathies.
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在硅胶和体内分析导致椎板病的氨基酸替换。
DOI：
10.3390/ijms222011226
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发表时间：
2021-10-18
影响因子：
5.6
通讯作者：
Wallrath LL
中科院分区：
文献类型：
--
作者：
Hinz BE;Walker SG;Xiong A;Gogal RA;Schnieders MJ;Wallrath LL
LMNA基因的突变会导致被称为核纤层蛋白病的疾病。LMNA编码核纤层蛋白A和C，在核膜中具有多种作用的中间丝。LMNA突变通常是单碱基变化，导致影响肌肉、神经和脂肪的多种疾病表型。疾病相关的氨基酸取代映射到三维结构的核纤层蛋白A/C，揭示没有明显的基因型-表型连接。计算机模拟分析显示，在Ig样折叠结构域中的9个预测伴侣蛋白结合口袋中有7个对应于疾病相关氨基酸取代的位点。核纤层蛋白A/C内相同位置的不同氨基酸取代引起不同的疾病，提出了氨基酸取代的性质或遗传背景差异是否有助于疾病表型的问题。视杆结构域中R249处的取代导致不同严重程度的肌营养不良。为了解决这种变异性，我们在果蝇核纤层蛋白C（LMNA的直系同源物）中建模了R249 Q和R249 W。幼虫体壁肌肉表达突变核纤层蛋白C导致异常核形态和过早死亡。当在间接飞行肌肉中表达时，R249 W比R249 Q引起更多的具有翼姿势缺陷的成年人，这与R249 W和R249 Q引起不同的肌营养不良症的观察结果一致，其中R249 W更严重。在这种情况下，氨基酸替代的性质似乎决定了肌肉疾病的严重程度。总之，我们的研究结果说明了果蝇预测肌肉疾病的严重程度和致病性的未知意义的变体的效用。
Mutations in the LMNA gene cause diseases called laminopathies. LMNA encodes lamins A and C, intermediate filaments with multiple roles at the nuclear envelope. LMNA mutations are frequently single base changes that cause diverse disease phenotypes affecting muscles, nerves, and fat. Disease-associated amino acid substitutions were mapped in silico onto three-dimensional structures of lamin A/C, revealing no apparent genotype–phenotype connections. In silico analyses revealed that seven of nine predicted partner protein binding pockets in the Ig-like fold domain correspond to sites of disease-associated amino acid substitutions. Different amino acid substitutions at the same position within lamin A/C cause distinct diseases, raising the question of whether the nature of the amino acid replacement or genetic background differences contribute to disease phenotypes. Substitutions at R249 in the rod domain cause muscular dystrophies with varying severity. To address this variability, we modeled R249Q and R249W in Drosophila Lamin C, an orthologue of LMNA. Larval body wall muscles expressing mutant Lamin C caused abnormal nuclear morphology and premature death. When expressed in indirect flight muscles, R249W caused a greater number of adults with wing posturing defects than R249Q, consistent with observations that R249W and R249Q cause distinct muscular dystrophies, with R249W more severe. In this case, the nature of the amino acid replacement appears to dictate muscle disease severity. Together, our findings illustrate the utility of Drosophila for predicting muscle disease severity and pathogenicity of variants of unknown significance.
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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：
9.9
作者：
Felice, KJ;Schwartz, RC;Grunnet, ML
通讯作者：
Grunnet, ML
影响因子：
4.6
作者：
Dialynas, George;Speese, Sean;Wallrath, Lori L.
通讯作者：
Wallrath, Lori L.
影响因子：
2.7
作者：
Fortier, TA;Vasa, PP;Woodard, CT
通讯作者：
Woodard, CT
影响因子：
4.5
作者：
Dialynas G;Shrestha OK;Ponce JM;Zwerger M;Thiemann DA;Young GH;Moore SA;Yu L;Lammerding J;Wallrath LL
通讯作者：
Wallrath LL