Unknown

Dataset Information

0

Molecular and cellular basis of hyperassembly and protein aggregation driven by a rare pathogenic mutation in DDX3X.


ABSTRACT: Current studies estimate that 1-3% of females with unexplained intellectual disability (ID) present de novo splice 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-linked DDX3X L556S mutation as a disorder arising from protein misfolding and aggregation.

SUBMITTER: de Castro Fonseca M 

PROVIDER: S-EPMC8335631 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC7083973 | biostudies-literature
| S-EPMC2359781 | biostudies-literature
| S-EPMC2274891 | biostudies-literature
| S-EPMC5296656 | biostudies-literature
| S-EPMC5391754 | biostudies-literature
| S-EPMC3974339 | biostudies-other
| S-EPMC7404254 | biostudies-literature
| S-EPMC2863246 | biostudies-literature
| S-EPMC10562560 | biostudies-literature
| S-EPMC9142813 | biostudies-literature