ArticleAmerican journal of human genetics2019
Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual Disability and Dysmorphic Features and Lead to P-Body Defects and RNA Dysregulation.
Article in American journal of human genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 84 citations in OpenAlex.
- P-body-mediated RNA decay controls neural crest EMT.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Genome-wide analysis of social behaviour across social domains, reporters and developmental stages: a meta-regression approach.Nature human behaviour · 2026Article
- Article
- De novo and inherited variants in DDX39B cause a novel neurodevelopmental syndrome.Brain : a journal of neurology · 2025Article
- DEAD/DEAH-box RNA helicases shape the risk of neurodevelopmental disorders.Trends in genetics : TIG · 2025Review
- Monoallelic de novo variants in DDX17 cause a neurodevelopmental disorder.Brain : a journal of neurology · 2025Article
- DDX3X syndrome: From clinical phenotypes to biological insights.Journal of neurochemistry · 2024Review
- DDX6 modulates P-body and stress granule assembly, composition, and docking.The Journal of cell biology · 2024Article
- Me31B: a key repressor in germline regulation and beyond.Bioscience reports · 2024Review
- Epigenetic silencing ofEpigenomics · 2024Article
- The role of DEAD- and DExH-box RNA helicases in neurodevelopmental disorders.Frontiers in molecular neuroscience · 2024Review
- SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis.Brain : a journal of neurology · 2023Article
- Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases.Signal transduction and targeted therapy · 2023Review
- Review
- Cellular functions of eukaryotic RNA helicases and their links to human diseases.Nature reviews. Molecular cell biology · 2023Review
- RNA helicase DDX6 and scaffold protein GW182 in P-bodies promote biogenesis of stress granules.Nucleic acids research · 2023Article
- Review
- Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease.American journal of human genetics · 2023Article
- Depletion of the RNA-binding protein PURA triggers changes in posttranscriptional gene regulation and loss of P-bodies.Nucleic acids research · 2023Article
- RNA Helicase DDX6 Regulates A-to-I Editing and Neuronal Differentiation in Human Cells.International journal of molecular sciences · 2023Article
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Authors and funding
38 authors at 15 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The human RNA helicase DDX6 is an essential component of membrane-less organelles called processing bodies (PBs). PBs are involved in mRNA metabolic processes including translational repression via coordinated storage of mRNAs. Previous studies in human cell lines have implicated altered DDX6 in molecular and cellular dysfunction, but clinical consequences and pathogenesis in humans have yet to be described. Here, we report the identification of five rare de novo missense variants in DDX6 in probands presenting with intellectual disability, developmental delay, and similar dysmorphic features including telecanthus, epicanthus, arched eyebrows, and low-set ears. All five missense variants (p.His372Arg, p.Arg373Gln, p.Cys390Arg, p.Thr391Ile, and p.Thr391Pro) are located in two conserved motifs of the RecA-2 domain of DDX6 involved in RNA binding, helicase activity, and protein-partner binding. We use functional studies to demonstrate that the first variants identified (p.Arg373Gln and p.Cys390Arg) cause significant defects in PB assembly in primary fibroblast and model human cell lines. These variants' interactions with several protein partners were also disrupted in immunoprecipitation assays. Further investigation via complementation assays included the additional variants p.Thr391Ile and p.Thr391Pro, both of which, similarly to p.Arg373Gln and p.Cys390Arg, demonstrated significant defects in P-body assembly. Complementing these molecular findings, modeling of the variants on solved protein structures showed distinct spatial clustering near known protein binding regions. Collectively, our clinical and molecular data describe a neurodevelopmental syndrome associated with pathogenic missense variants in DDX6. Additionally, we suggest DDX6 join the DExD/H-box genes DDX3X and DHX30 in an emerging class of neurodevelopmental disorders involving RNA helicases.
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