ArticleAmerican journal of human genetics2018
Activating Mutations in PAK1, Encoding p21-Activated Kinase 1, Cause a Neurodevelopmental Disorder.
Article in American journal of human genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers, 1 of them a synthesis that pooled it.
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Who cites it
49 citing papers in PubMed, 1 synthesis or guideline pooled it, 73 citations in OpenAlex.
- Pooled it
- Development of NanoBRET Cellular Target Engagement Assays in Primary Neurons for Activating Mutants of p21-Activated Kinase 1.ACS chemical neuroscience · 2026Article
- Shared molecular pathways in pediatric genetic epilepsies: Insights from a single-center cohort of 80 patients.Epilepsia open · 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
- Molecular genotype-phenotype correlation in ACTB- and ACTG1-related non-muscle actinopathies.American journal of human genetics · 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
- PAK1 inhibitor NVS-PAK1-1 preserves dendritic spines in amyloid/tau exposed neurons and 5xFAD mice.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- PAK1 regulates oligodendroglial proliferation and repopulation in homeostatic and demyelinating brain.Cellular and molecular life sciences : CMLS · 2025Article
- LIMK1 variants are associated with divergent endocrinological phenotypes and altered exocytosis dynamics.iScience · 2025Article
- Phenotypic Expansion of Knobloch Syndrome Type 2 in an Individual With a De Novo PAK2 Variant.American journal of medical genetics. Part A · 2025Article
- PAK3 pathogenic variant associated with sleep-related hypermotor epilepsy in a family with parental mosaicism.Epilepsia open · 2025Article
- Antenatal phenotype associated with PAK2 pathogenic variants: bilateral pleural effusion as a warning sign.BMC medical genomics · 2025Article
- The molecular genetics of PI3K/PTEN/AKT/mTOR pathway in the malformations of cortical development.Genes & diseases · 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
- Mitochondrial bioenergetics, metabolism, and beyond in pancreatic β-cells and diabetes.Frontiers in molecular biosciences · 2024Review
- A ubiquitin-based effector-to-inhibitor switch coordinates early brain, craniofacial, and skin development.Nature communications · 2023Article
- Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants.European journal of human genetics : EJHG · 2023Review
- Targeting p21-activated kinase 1 for development of a novel anti-arrhythmic drug class.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
p21-activated kinases (PAKs) are serine/threonine protein kinases acting as effectors of CDC42 and RAC, which are members of the RHO family of small GTPases. PAK1's kinase activity is autoinhibited by homodimerization, whereas CDC42 or RAC1 binding causes PAK1 activation by dimer dissociation. Major functions of the PAKs include actin cytoskeleton reorganization, for example regulation of the cellular protruding activity during cell spreading. We report the de novo PAK1 mutations c.392A>G (p.Tyr131Cys) and c.1286A>G (p.Tyr429Cys) in two unrelated subjects with developmental delay, secondary macrocephaly, seizures, and ataxic gait. We identified enhanced phosphorylation of the PAK1 targets JNK and AKT in fibroblasts of one subject and of c-JUN in those of both subjects compared with control subjects. In fibroblasts of the two affected individuals, we observed a trend toward enhanced PAK1 kinase activity. By using co-immunoprecipitation and size-exclusion chromatography, we observed a significantly reduced dimerization for both PAK1 mutants compared with wild-type PAK1. These data demonstrate that the two PAK1 variants function as activating alleles. In a cell spreading assay, subject-derived fibroblasts showed significant enrichment in cells occupied by filopodia. Interestingly, application of the PAK1 inhibitor FRAX486 completely reversed this cellular phenotype. Together, our data reveal that dominantly acting, gain-of-function PAK1 mutations cause a neurodevelopmental phenotype with increased head circumference, possibly by a combined effect of defective homodimerization and enhanced kinase activity of PAK1. This condition, along with the developmental disorders associated with RAC1 and CDC42 missense mutations, highlight the importance of RHO GTPase members and effectors in neuronal development.
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Registered trials
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.