Novel NFkB1 heterozygous missense mutations involved in immunedysregulation
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PROVIDER: PRJEB46615 | ENA |
REPOSITORIES: ENA
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Project description:1 Novel Missense Variants in Patients with Primary Immunodeficiency and Immune dysregulation
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Project description:De novo mutations in the RNA binding protein DDX3X cause neurodevelopmental disorders including DDX3X syndrome and autism spectrum disorder. Amongst ~200 mutations identified to date, half are missense. While DDX3X loss of function is known to impair neural cell fate, how the landscape of missense mutations impacts neurodevelopment is almost entirely unknown. Here, we integrate transcriptomics, proteomics, and live imaging to demonstrate clinically diverse DDX3X missense mutations perturb neural development via distinct cellular and molecular mechanisms. Using mouse primary neural progenitors, we investigate four recurrently mutated DDX3X missense variants, from clinically severe (2) to mild (2). While clinically severe mutations impair neurogenesis, mild mutations have only a modest impact on cell fate. Moreover, expression of severe mutations leads to profound neuronal death. Using a proximity labeling screen in neural progenitors, we discover DDX3X missense variants have unique protein interactors. We observe notable overlap amongst severe mutations, suggesting common mechanisms underlying altered cell fate and survival. Transcriptomic analysis and subsequent cellular investigation highlights new pathways associated with DDX3X missense variants, including upregulated DNA Damage Response. Notably, clinically severe mutations exhibit excessive DNA damage in neurons, associated with aberrant cytoplasmic DNA:RNA hybrids and formation of stress granules. These findings highlight aberrant RNA metabolism and DNA damage in DDX3X-mediated neuronal cell death. In sum our findings reveal new mechanisms by which clinically distinct DDX3X missense mutations differentially impair neurodevelopment.
2025-01-06 | GSE279078 | GEO
Project description:Disruption of circadian rhythms increases the risk of several types of cancer. Mammalian cryptochromes (CRY1 and CRY2) are circadian transcriptional repressors that are related to DNA repair enzymes. While CRYs lack DNA repair activity, they modulate the transcriptional response to DNA damage, and CRY2 can promote SCFFBXL3-mediated ubiquitination of c-MYC and other targets. Here, we characterize five mutations in CRY2 observed in human cancers in The Cancer Genome Atlas. We demonstrate that two orthologous mutations of mouse CRY2 (D325H and S510L) accelerate the growth of primary mouse fibroblasts expressing high levels of c-MYC. Neither mutant affects steady state levels of overexpressed c-MYC, and they have divergent impacts on circadian rhythms and on the ability of CRY2 to interact with SCFFBXL3. Unexpectedly, stable expression of either CRY2 D325H or of CRY2 S510L robustly suppresses P53 target gene expression, suggesting that this is the primary mechanism by which they influence cell growth.
2021-06-16 | GSE165647 | GEO
Project description:Proteomic and phosphoproteomic data for rare HER2 missense mutations
2023-03-20 | PXD040988 |
Project description:PTEN plays a crucial role in preventing the development of glioblastoma (GBM), a severe and untreatable brain cancer. In GBM, most PTEN deficiencies arise from missense mutations, many of which have not been thoroughly examined. Here, we leveraged genetically modified mice and matched isogenic astrocyte cell cultures to investigate how specific and clinically relevant PTEN mutations (G36E, L42R, C105F, and R173H) behave in the development of GBM driven by EGFR. We report that the tumor-suppressive abilities of these PTEN mutants do not depend on their ability to act as lipid phosphatases but are instead related to their increased presence at the cell membrane. Moreover, these PTEN mutations led to heightened EGFR activity by keeping EGFR within endomembranes longer, affecting its signaling behavior. Through comprehensive studies on global protein phosphorylation and kinase library analyses in cells with the G36E and L42R PTEN mutations, we identified distinct cancer-promoting pathways activated by EGFR, offering new targets for treating GBM with these PTEN alterations.
2025-05-06 | PXD051485 | Pride
Project description: Not available
| S-EPMC8246418 | biostudies-literature
Project description:The outcome for children with high-grade gliomas (HGG) remains dismal, with a two-year survival rate of only 10-30%. Approximately half of pediatric HGGs are diffuse intrinsic pontine glioma (DIPG), a brainstem tumor that arises almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet derived growth factor receptor alpha (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs. To determine whether the PDGFRA is also targeted by more subtle mutations not detected by copy number analysis, we sequenced all PDGFRA coding exons from a cohort of pediatric HGGs. Somatic activating mutations were identified in 14.4% (13/90) of non-brainstem pediatric HGGs and 4.7% (2/43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. 40% of tumors with mutation showed concurrent amplification, while 60% carried heterozygous mutations. Six different mutations impacting different domains all resulted in ligand-independent receptor activation that was blocked by small molecule inhibitors of PDGFR. Expression of mutants in p53-null primary mouse astrocytes conferred a proliferative advantage in vitro, and generated HGGs in vivo with complete penetrance when implanted into brain. The gene expression signatures reflected the spectrum of human diffuse HGGs. PDGFRA intragenic deletion of exons 8 and 9 were previously shown in adult HGG, but were not detected in 83 non-brainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFR in childhood HGG. To better understand the consequence of PDGFRα mutation in pediatric gliomagenesis, retroviral constructs expressing wild-type PDGFRα or six selected PDGFRα mutants that affect different regions of the receptor were generated for functional studies. p53-null primary mouse astrocyte (PMA) cultures were chosen as a relevant cellular background to assess PDGFRα function.
2013-11-06 | E-GEOD-46190 | biostudies-arrayexpress
Project description:The derivation of microglia from human pluripotent stem cells provides systems for understanding microglial biology and enables functional studies of neurological disease-causing mutations. We describe a robust method for the derivation and maintenance of microglia from human stem cells, which are phenotypically and functionally comparable to primary human microglia. We used stem cell-derived microglia to study the consequences of missense mutations in the microglial-expressed protein Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which are causal for a frontotemporal dementia-like (FTD-like) syndrome and Nasu-Hakola disease (NHD). While many ligands and functions for TREM2 have been described, it is not known how TREM2 signalling dysregulation affects specific elements of microglial biology to influence disease pathogenesis. We find that mutant TREM2 accumulates in its immature form, does not undergo typical proteolysis, and is not properly trafficked to the plasma membrane of patient-derived microglia. However, in the absence of plasma membrane TREM2, microglia differentiate normally, respond to stimulation with lipopolysaccharide, and are phagocytically competent. These data indicate that dementia-associated TREM2 mutations have subtle effects on microglia biology, consistent with the late adult-onset of disease in individuals with these mutations.
2018-04-03 | GSE110952 | GEO