Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization.
Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization.
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破坏NF1变体通过神经纤维蛋白二聚化以主要的负方式作用。
DOI：
10.1073/pnas.2208960120
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发表时间：
2023-01-31
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
本研究描述了一个模型的严重表型的患者神经纤维瘤病1型（NF 1）所造成的特定的错义突变。我们表明，这些突变作为显性负突变体，通过与野生型神经纤维蛋白的二聚化，并使用我们新解决的神经纤维蛋白二聚体的cryo-EM结构来解释为什么这些突变破坏蛋白质结构，并预测和验证其他患者的变体。到目前为止，NF 1疾病的基因型-表型关系很少，尽管鉴定了2000多个致病性变体。密码子844至848处的突变表现出严重的表型，但其作用机制尚不清楚。这项工作对临床管理和理解疾病中神经纤维蛋白功能丧失具有重要意义。I型神经纤维瘤病（NF 1）基因中的大多数致病性突变通过过早截短或微缺失降低总神经纤维蛋白表达，但对功能丧失的错义变体如何驱动NF 1疾病的了解较少。我们已经发现，与严重表型相关的密码子844至848中的患者变体引起蛋白质不稳定性并发挥额外的显性负作用，由此野生型神经纤维蛋白也通过蛋白质二聚化变得不稳定。我们已经使用我们的神经纤维蛋白低温电子显微镜结构来预测和验证通过类似机制起作用的其他患者变体。这为理解基因型-表型相关性提供了基础，并对患者咨询，疾病管理和治疗具有重要意义。
This study describes a model for the severe phenotype of patients with Neurofibromatosis Type 1 (NF1) caused by specific missense mutations. We show, that these mutations act as dominant negative mutants, through dimerization with wild-type neurofibromin, and use our newly solved cryo-EM structure of the neurofibromin dimer to explain why these mutations disrupt protein structure and to predict and validate other patient variants. Until now, there have been very few genotype–phenotype relationships for the NF1 disease, despite the identification of more than two thousand pathogenic variants. Mutations at codons 844 to 848 exhibit a severe phenotype, but the mechanism for their action was not known. This work has important implications for clinical management and understanding neurofibromin loss-of-function in disease. The majority of pathogenic mutations in the neurofibromatosis type I (NF1) gene reduce total neurofibromin protein expression through premature truncation or microdeletion, but it is less well understood how loss-of-function missense variants drive NF1 disease. We have found that patient variants in codons 844 to 848, which correlate with a severe phenotype, cause protein instability and exert an additional dominant-negative action whereby wild-type neurofibromin also becomes destabilized through protein dimerization. We have used our neurofibromin cryogenic electron microscopy structure to predict and validate other patient variants that act through a similar mechanism. This provides a foundation for understanding genotype–phenotype correlations and has important implications for patient counseling, disease management, and therapeutics.
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影响因子：
13.8
作者：
Boyd, Kevin P.;Gao, Liyan;Feng, Rui;Beasley, Mark;Messiaen, Ludwine;Korf, Bruce R.;Theos, Amy
通讯作者：
Theos, Amy
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
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Hassabis D
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影响因子：
48
作者：
Li, Xueming;Mooney, Paul;Zheng, Shawn;Booth, Christopher R.;Braunfeld, Michael B.;Gubbens, Sander;Agard, David A.;Cheng, Yifan
通讯作者：
Cheng, Yifan
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.9
作者：
Long, Ashlee;Liu, Hui;Wallis, Deeann
通讯作者：
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