Modeling Pathogenic Variants in the RNA Exosome.
Modeling Pathogenic Variants in the RNA Exosome.
复制标题
DOI：
--
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Morton DJ
中科院分区：
文献类型：
--
作者：
de Amorim J;Slavotinek A;Fasken MB;Corbett AH;Morton DJ
外泌体病是由编码RNA外泌体复合物（EXOSC）的结构亚基的基因突变引起的罕见疾病的集合。RNA外泌体对于加工和降解许多RNA靶标都至关重要。单个RNA外泌体亚基基因（称为EXOSC基因）的突变与多种不同的疾病有关。这些外泌体病不是由EXOSC基因中的纯合功能丧失或大缺失引起的，可能是因为一定水平的RNA外泌体活性对生存力至关重要。因此，迄今为止描述的所有患者都具有至少一个具有错义突变的等位基因，所述错义突变编码具有与疾病相关的单个致病性氨基酸变化的RNA外泌体亚基。了解这些变化如何导致这类疾病报告的不同临床表现，需要研究个体致病性错义变体如何改变RNA外泌体功能。这些研究将需要获得患者样本，这对这些非常罕见的疾病来说是一个挑战，同时还要对患者变异进行建模。在这里，我们重点介绍了最近的五项研究，这些研究模拟了EXOSC 3、EXOSC 2和EXOSC 5中的致病性变体。
Exosomopathies are a collection of rare diseases caused by mutations in genes that encode structural subunits of the RNA exosome complex (EXOSC). The RNA exosome is critical for both processing and degrading many RNA targets. Mutations in individual RNA exosome subunit genes (termed EXOSC genes) are linked to a variety of distinct diseases. These exosomopathies do not arise from homozygous loss-of-function or large deletions in the EXOSC genes likely because some level of RNA exosome activity is essential for viability. Thus, all patients described so far have at least one allele with a missense mutation encoding an RNA exosome subunit with a single pathogenic amino acid change linked to disease. Understanding how these changes lead to the disparate clinical presentations that have been reported for this class of diseases necessitates investigation of how individual pathogenic missense variants alter RNA exosome function. Such studies will require access to patient samples, a challenge for these very rare diseases, coupled with modeling the patient variants. Here, we highlight five recent studies that model pathogenic variants in EXOSC3, EXOSC2, and EXOSC5.