Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations.
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 m...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2025-01-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1011555 |
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| author | Federica Mosti Mariah L Hoye Carla F Escobar-Tomlienovich Debra L Silver |
| author_facet | Federica Mosti Mariah L Hoye Carla F Escobar-Tomlienovich Debra L Silver |
| author_sort | Federica Mosti |
| collection | DOAJ |
| 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, spanning 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 increased 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. |
| format | Article |
| id | doaj-art-6fce117c423744e78402ff8fc2eba6b2 |
| institution | Kabale University |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-6fce117c423744e78402ff8fc2eba6b22025-02-06T05:30:27ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042025-01-01211e101155510.1371/journal.pgen.1011555Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations.Federica MostiMariah L HoyeCarla F Escobar-TomlienovichDebra L SilverDe 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, spanning 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 increased 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.https://doi.org/10.1371/journal.pgen.1011555 |
| spellingShingle | Federica Mosti Mariah L Hoye Carla F Escobar-Tomlienovich Debra L Silver Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations. PLoS Genetics |
| title | Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations. |
| title_full | Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations. |
| title_fullStr | Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations. |
| title_full_unstemmed | Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations. |
| title_short | Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations. |
| title_sort | multi modal investigation reveals pathogenic features of diverse ddx3x missense mutations |
| url | https://doi.org/10.1371/journal.pgen.1011555 |
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