ArticleAmerican journal of human genetics2017
RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes.
Article in American journal of human genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 95 papers.
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Who cites it
95 citing papers in PubMed, 164 citations in OpenAlex.
- Review
- The role of Rho GTPases in facial morphogenesis.Developmental dynamics : an official publication of the American Association of Anatomists · 2026Review
- Epilepsy-associated digenic variants affecting an actin/mitochondria/glutamate pathway promote seizure susceptibility.The Journal of clinical investigation · 2026Article
- A matter of switch: how RAC1 variants drive distinct disorders.European journal of human genetics : EJHG · 2026Article
- Autism-linked protein POSH balances NMDAR signaling via a self-limiting kinase-scaffold loop.iScience · 2026Article
- Distinct sub-clusters of developmental disorder-associated variants in the switch II region of RAC1.European journal of human genetics : EJHG · 2026Article
- KCNA2 variants cause dilated cardiomyopathy, obesity and sleep apnea through RAC-ERK pathway.EMBO molecular medicine · 2026Article
- ARP2/3 complex mediates the neuropathology of PTEN-deficient human neural cells downstream of mTORC1 and mTORC2 hyperactivation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Molecular genotype-phenotype correlation in ACTB- and ACTG1-related non-muscle actinopathies.American journal of human genetics · 2026Article
- Mouse scalp development requires Rac1 and SRF for the maintenance of mechanoresponsive mesenchyme.Development (Cambridge, England) · 2025Article
- Article
- Proteomic profiling of small extracellular vesicles from bovine nucleus pulposus cells.PloS one · 2025Article
- The p.R66W Variant inCells · 2024Article
- The role of RAC1 in resistance to targeted therapies in cancer.Small GTPases · 2024Review
- Deleterious ZNRF3 germline variants cause neurodevelopmental disorders with mirror brain phenotypes via domain-specific effects on Wnt/β-catenin signaling.American journal of human genetics · 2024Article
- The molecular genetics of PI3K/PTEN/AKT/mTOR pathway in the malformations of cortical development.Genes & diseases · 2024Review
- Genes Co-Expressed withInternational journal of molecular sciences · 2024Article
- ARHGAP4 variants are associated with X-linked early-onset temporal lobe epilepsy.World journal of pediatrics : WJP · 2024Article
- Loss of the polarity protein Par3 promotes dendritic spine neoteny and enhances learning and memory.iScience · 2024Article
- The Small G-Protein Rac1 in the Dorsomedial Striatum Promotes Alcohol-Dependent Structural Plasticity and Goal-Directed Learning in Mice.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
35 more citing papers are in PubMed but not listed here.
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22 authors at 12 institutions in 5 countries.
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Abstract
RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between -2.5 to -5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of ∼10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.
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