ArticleBrain : a journal of neurology2019
De novo variants in PAK1 lead to intellectual disability with macrocephaly and seizures.
Article in Brain : a journal of neurology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 46 citations in OpenAlex.
- Development of NanoBRET Cellular Target Engagement Assays in Primary Neurons for Activating Mutants of p21-Activated Kinase 1.ACS chemical neuroscience · 2026Article
- Development of NanoBRET cellular target engagement assays in primary neurons for activating mutants of p21-activated kinase 1.bioRxiv : the preprint server for biology · 2026Article
- PAK1 (p21-Activated Kinase 1) and Its Role in Neurodevelopmental Disorders-New Case Report and a Comprehensive Review.International journal of molecular sciences · 2025Review
- Differential microRNA profiling of blood L1CAM and bulk extracellular vesicles in bipolar disorder.Epigenomics · 2025Article
- PAK1 Is Involved in Epileptogenesis by Regulating the Synaptic Plasticity of Hippocampal Neurons Through LIMK.Neurochemical research · 2025Article
- PAK1 regulates oligodendroglial proliferation and repopulation in homeostatic and demyelinating brain.Cellular and molecular life sciences : CMLS · 2025Article
- PAK3 pathogenic variant associated with sleep-related hypermotor epilepsy in a family with parental mosaicism.Epilepsia open · 2025Article
- An in-depth review of the function of RNA-binding protein FXR1 in neurodevelopment.Cell and tissue research · 2024Review
- PAK3 activation promotes the tangential to radial migration switch of cortical interneurons by increasing leading process dynamics and disrupting cell polarity.Molecular psychiatry · 2024Article
- Loss of the polarity protein Par3 promotes dendritic spine neoteny and enhances learning and memory.iScience · 2024Article
- Control of OPC proliferation and repopulation by the intellectual disability gene PAK1 under homeostatic and demyelinating conditions.bioRxiv : the preprint server for biology · 2024Article
- Computational analysis of protein-protein interactions of cancer drivers in renal cell carcinoma.FEBS open bio · 2024Article
- PLPP/CIN-mediated NF2 S10 dephosphorylation distinctly regulates kainate-induced seizure susceptibility and neuronal death through PAK1-NF-κB-COX-2-PTGES2 signaling pathway.Journal of neuroinflammation · 2023Article
- Neurodevelopmental disorders, like cancer, are connected to impaired chromatin remodelers, PI3K/mTOR, and PAK1-regulated MAPK.Biophysical reviews · 2023Review
- A de novo PAK1 likely pathogenic variant and a de novo terminal 1q microdeletion in a Chinese girl with global developmental delay, severe intellectual disability, and seizures.BMC medical genomics · 2023Article
- Comparing synaptic proteomes across five mouse models for autism reveals converging molecular similarities including deficits in oxidative phosphorylation and Rho GTPase signaling.Frontiers in aging neuroscience · 2023Article
- Cdc42 Regulates the Expression of Cytoskeleton and Microtubule Network Proteins to Promote Invasion and Metastasis of Progeny Cells Derived from CoClJournal of Cancer · 2023Article
- Interneuron odyssey: molecular mechanisms of tangential migration.Frontiers in neural circuits · 2023Review
- The molecular basis of p21-activated kinase-associated neurodevelopmental disorders: From genotype to phenotype.Frontiers in neuroscience · 2023Review
- Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes.Brain : a journal of neurology · 2022Article
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Authors and funding
21 authors at 12 institutions in 4 countries.
Funding
Abstract
Using trio exome sequencing, we identified de novo heterozygous missense variants in PAK1 in four unrelated individuals with intellectual disability, macrocephaly and seizures. PAK1 encodes the p21-activated kinase, a major driver of neuronal development in humans and other organisms. In normal neurons, PAK1 dimers reside in a trans-inhibited conformation, where each autoinhibitory domain covers the kinase domain of the other monomer. Upon GTPase binding via CDC42 or RAC1, the PAK1 dimers dissociate and become activated. All identified variants are located within or close to the autoinhibitory switch domain that is necessary for trans-inhibition of resting PAK1 dimers. Protein modelling supports a model of reduced ability of regular autoinhibition, suggesting a gain of function mechanism for the identified missense variants. Alleviated dissociation into monomers, autophosphorylation and activation of PAK1 influences the actin dynamics of neurite outgrowth. Based on our clinical and genetic data, as well as the role of PAK1 in brain development, we suggest that gain of function pathogenic de novo missense variants in PAK1 lead to moderate-to-severe intellectual disability, macrocephaly caused by the presence of megalencephaly and ventriculomegaly, (febrile) seizures and autism-like behaviour.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.