文章基本信息

标题：Molecular and cellular basis of hyperassembly and protein aggregation driven by a rare pathogenic mutation in DDX3X
本地全文：下载
作者：Matheus de Castro Fonseca ; Juliana Ferreira de Oliveira ; Bruno Henrique Silva Araujo 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：8
页码：1-28
DOI：10.1016/j.isci.2021.102841
语种：English
出版社：Elsevier
摘要：SummaryCurrent studies estimate that 1–3% of females with unexplained intellectual disability (ID) presentde novosplice site, nonsense, frameshift, or missense mutations in the DDX3X protein (DEAD-Box Helicase 3 X-Linked). However, the cellular and molecular mechanisms by which DDX3X mutations impair brain development are not fully comprehended. Here, we show that the ID-linked missense mutation L556S renders DDX3X prone to aggregation. By using a combination of biophysical assays and imaging approaches, we demonstrate that this mutant assembles solid-like condensates and amyloid-like fibrils. Although we observed greatly reduced expression of the mutant allele in a patient who exhibits skewed X inactivation, this appears to be enough to sequestrate healthy proteins into solid-like ectopic granules, compromising cell function. Therefore, our data suggest ID-linkedDDX3XL556S mutation as a disorder arising from protein misfolding and aggregation.Graphical abstractDisplay OmittedHighlights•DDX3Xmutations skew X-inactivation and are found in 1-3% of unexplained ID in females•DDX3X mutant proteins assemble solid-like condensates and amyloid-like fibrils•Aberrant granules formed by DDX3X mutants sequestrate healthy DDX3X protein•ID-linked DDX3X L556S mutation decreases cell viability and induces apoptosisMolecular biology; Neuroscience; Biophysics