Genetic variation associated with condensate dysregulation in disease.
Genetic variation associated with condensate dysregulation in disease.
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DOI：
10.1016/j.devcel.2022.06.010
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发表时间：
2022-07-25
影响因子：
11.8
通讯作者：
Young, Richard A.
中科院分区：
文献类型：
--
作者：
Banani, Salman F.;Afeyan, Lena K.;Hawken, Susana W.;Henninger, Jonathan E.;Dall'Agnese, Alessandra;Clark, Victoria E.;Platt, Jesse M.;Oksuz, Ozgur;Hannett, Nancy M.;Sagi, Ido;Lee, Tong Ihn;Young, Richard A.
许多细胞过程涉及生物分子凝集物，这导致了不同的致病突变可能扰乱凝集物的调节。虽然概念验证研究已经确定了导致凝析油失调的特定突变，但影响凝析油的病理性遗传变异的全部范围尚不清楚。在这里，我们全面地将致病突变与假定的凝析油形成蛋白中的凝析油促进蛋白特征进行映射，并发现超过36,000个致病突变，这些突变可信地导致1200多种孟德尔疾病和550例癌症中的凝析油失调。这一资源捕获了目前已知的冷凝物失调突变，实验测试证实，额外的病理突变确实会影响细胞中的冷凝物特性。这些发现表明，凝集物失调可能是一种普遍存在的致病机制，在人类广泛的疾病中，为识别病理改变的凝集物中涉及的蛋白质和突变提供了一种策略，并作为对疾病和治疗假说的机械性见解的基础。Banani等人。将36,000个致病突变映射到蛋白质中促进凝集的特征。这些数据预测，超过1000种蛋白质参与了疾病中凝集物的失调调节，为研究凝集物在疾病中的作用及其潜在的治疗应用提供了基础。
A multitude of cellular processes involve biomolecular condensates, which has led to the suggestion that diverse pathogenic mutations may dysregulate condensates. While proof-of-concept studies have identified specific mutations that cause condensate dysregulation, the full scope of pathological genetic variation that affects condensates is not yet known. Here we comprehensively map pathogenic mutations to condensate-promoting protein features in putative condensate-forming proteins and find over 36,000 pathogenic mutations that plausibly contribute to condensate dysregulation in over 1,200 Mendelian diseases and 550 cancers. This resource captures mutations presently known to dysregulate condensates and experimental tests confirm that additional pathological mutations do indeed affect condensate properties in cells. These findings suggest that condensate dysregulation may be a pervasive pathogenic mechanism underlying a broad spectrum of human diseases, provide a strategy to identify proteins and mutations involved in pathologically altered condensates, and serve as a foundation for mechanistic insights into disease and therapeutic hypotheses. Banani et al. map 36,000 pathogenic mutations to condensate-promoting features in proteins. The data lead to a prediction that more than 1,000 proteins are involved in condensate dysregulation in disease, providing a foundation for investigating the roles of condensates in disease and their potential therapeutic applications.
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