Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Dev Cell. 2022 Jul 25;57(14):1776-1788.e8. doi: 10.1016/j.devcel.2022.06.010. Epub 2022 Jul 8.
A multitude of cellular processes involve biomolecular condensates, which has led to the suggestion that diverse pathogenic mutations may dysregulate condensates. Although proof-of-concept studies have identified specific mutations that cause condensate dysregulation, the full scope of the 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.
大量的细胞过程涉及生物分子凝聚物，这导致了这样一种观点，即多种致病突变可能会扰乱凝聚物。尽管概念验证研究已经确定了导致凝聚物失调的特定突变，但影响凝聚物的病理遗传变异的全部范围尚不清楚。在这里，我们将致病突变全面映射到潜在凝聚物形成蛋白中的凝聚物促进蛋白特征上，发现了超过 36000 种致病突变，这些突变可能导致 1200 多种孟德尔疾病和 550 多种癌症中的凝聚物失调。该资源捕获了目前已知扰乱凝聚物的突变，实验测试证实，其他病理突变确实会影响细胞中凝聚物的性质。这些发现表明，凝聚物失调可能是广泛存在于多种人类疾病中的一种普遍致病机制，为识别与病理改变凝聚物相关的蛋白和突变提供了一种策略，并为深入了解疾病和治疗假说提供了机制见解的基础。
