Delineation of functionally essential protein regions for 242 neurodevelopmental genes.
Delineation of functionally essential protein regions for 242 neurodevelopmental genes.
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针对242个神经发育基因的功能性蛋白质区域的描述。
DOI：
10.1093/brain/awac381
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发表时间：
2023-02-13
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神经发育障碍(NDDS)，包括严重的儿科癫痫、自闭症和智力残疾，是临床基因检测经常可以确定致病变异的异质性疾病。对他们中的许多人来说，基因疗法将在今年或未来几年的临床试验中进行测试。与第一代对症治疗不同，新的治疗疾病的精确药物需要在患者进入临床试验之前进行基因测试知情诊断。然而，即使在2022年，大多数已确定的新城疫基因的遗传变异都是“意义不确定的变异”。为了安全地招募患者参加精确医学临床试验，重要的是增加我们对NDD相关蛋白中哪些区域可以“容忍”错义变异，哪些区域是“必需的”，并在突变时会导致NDD的知识。此外，关于蛋白质三维结构中功能不可或缺的区域的知识也可以为疾病变异的分子机制提供洞察力。我们开发了一种新的共识方法，该方法覆盖了基于进化和种群的基因组分数来识别蛋白质结构上的3D必需位置(Essential3D)。在对AlphaFold预测和实验解决的蛋白质结构进行了广泛的基准测试后，我们为242个NDD生成了目前最大的专家精选蛋白质结构集，并在189个基因紊乱相关蛋白质中确定了14 377个Essential3D位点。我们证明，与单一注释相比，Essential3D站点的共识注释改进了疾病突变的优先顺序。识别出的必需3D位点丰富了膜间区或活性位点等功能特征，并在蛋白质复合体中发现了关键的分子间相互作用，否则没有被注释。使用目前最大的自闭症、发育障碍和癫痫外显子序列研究，包括360,000名NDD患者和人群对照，我们发现Essential3D位点的错义变体在患者中丰富了8倍。综上所述，我们开发了242个NDD的全面蛋白质结构集，并在其中确定了14377个必需3D位点。所有数据都可以在https://es-ndd.broadinstitute.org上获得，以进行交互式视觉检查，以加强对242个NDDS基因的变种解释和机制假说的发展。所提供的资源将加强临床变异解释和新城疫相关基因和编码蛋白的电子药物靶点开发。Iqbal等人。生成一个新的共识注释14,377个蛋白质残基的3D(‘基本3D位点’；https://es-ndd.broadinstitute.org/)的189个神经发育障碍相关的蛋白质，并表明，在外显子组测序研究中发现的位置是患者的8倍丰富的360,000名患者和人群对照。有关本文的科学评论，请参阅科斯坦和安德拉德(https://doi.org/10.1093/brain/awad011))。
Neurodevelopmental disorders (NDDs), including severe paediatric epilepsy, autism and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial. However, even in 2022, most identified genetic variants in NDD genes are ‘variants of uncertain significance’. To safely enrol patients in precision medicine clinical trials, it is important to increase our knowledge about which regions in NDD-associated proteins can ‘tolerate’ missense variants and which ones are ‘essential’ and will cause a NDD when mutated. In addition, knowledge about functionally indispensable regions in the 3D structure context of proteins can also provide insights into the molecular mechanisms of disease variants. We developed a novel consensus approach that overlays evolutionary, and population based genomic scores to identify 3D essential sites (Essential3D) on protein structures. After extensive benchmarking of AlphaFold predicted and experimentally solved protein structures, we generated the currently largest expert curated protein structure set for 242 NDDs and identified 14 377 Essential3D sites across 189 gene disorders associated proteins. We demonstrate that the consensus annotation of Essential3D sites improves prioritization of disease mutations over single annotations. The identified Essential3D sites were enriched for functional features such as intermembrane regions or active sites and discovered key inter-molecule interactions in protein complexes that were otherwise not annotated. Using the currently largest autism, developmental disorders, and epilepsies exome sequencing studies including >360 000 NDD patients and population controls, we found that missense variants at Essential3D sites are 8-fold enriched in patients. In summary, we developed a comprehensive protein structure set for 242 NDDs and identified 14 377 Essential3D sites in these. All data are available at https://es-ndd.broadinstitute.org for interactive visual inspection to enhance variant interpretation and development of mechanistic hypotheses for 242 NDDs genes. The provided resources will enhance clinical variant interpretation and in silico drug target development for NDD-associated genes and encoded proteins. Iqbal et al. generate a new consensus annotation of 14,377 protein residues in 3D (‘Essential3D sites’; https://es-ndd.broadinstitute.org/) across 189 neurodevelopmental disorder-associated proteins and show that the identified sites are 8-fold enriched in patients in exome-sequencing studies with >360,000 patients and population controls. See Costain and Andrade (https://doi.org/10.1093/brain/awad011) for a scientific commentary on this article.
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错义突变热点识别神经发育障碍基因和功能域
影响因子：
25
作者：
Geisheker MR;Heymann G;Wang T;Coe BP;Turner TN;Stessman HAF;Hoekzema K;Kvarnung M;Shaw M;Friend K;Liebelt J;Barnett C;Thompson EM;Haan E;Guo H;Anderlid BM;Nordgren A;Lindstrand A;Vandeweyer G;Alberti A;Avola E;Vinci M;Giusto S;Pramparo T;Pierce K;Nalabolu S;Michaelson JJ;Sedlacek Z;Santen GWE;Peeters H;Hakonarson H;Courchesne E;Romano C;Kooy RF;Bernier RA;Nordenskjöld M;Gecz J;Xia K;Zweifel LS;Eichler EE
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影响因子：
6.3
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影响因子：
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Al Mehdi, Krami;Benhnini, Fouad;Halima, Nahili
通讯作者：
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