ArticleAmerican journal of human genetics2022
Loss-of-function variants in TIAM1 are associated with developmental delay, intellectual disability, and seizures.
Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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24 citing papers in PubMed, 39 citations in OpenAlex.
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- Further characterization of the BRSK2-associated neurodevelopmental disorder.European journal of human genetics : EJHG · 2026Article
- A retrograde, non-canonical integrated stress response cascade maintains synaptic strength under amino acid deprivation.Cell reports · 2025Article
- Heterozygous variants ineLife · 2025Article
- Functional assays inGenome research · 2025Review
- Molecular organization of central cholinergic synapses.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- De novo variants in CDKL1 and CDKL2 are associated with neurodevelopmental symptoms.American journal of human genetics · 2025Article
- Topographic Axes of Wiring Space Converge to Genetic Topography in Shaping the Human Cortical Layout.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Single-nucleus RNA sequencing: immature excitatory neurons and transformed glia build human BRAFBrain communications · 2025Article
- Article
- Homozygous missense variants in YKT6 result in loss of function and are associated with developmental delay, with or without severe infantile liver disease and risk for hepatocellular carcinoma.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- RhoGEF Tiam2 Regulates Glutamatergic Synaptic Transmission in Hippocampal CA1 Pyramidal Neurons.eNeuro · 2024Article
- De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features.American journal of human genetics · 2024Article
- Genomic analysis of 116 autism families strengthens known risk genes and highlights promising candidates.NPJ genomic medicine · 2024Article
- Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans.Nature reviews. Genetics · 2024Review
- Allelic strengths of encephalopathy-associatedeLife · 2023Article
- miR-590-5p/Tiam1-mediated glucose metabolism promotes malignant evolution of pancreatic cancer by regulating SLC2A3 stability.Cancer cell international · 2023Article
- Whole genome analysis of rare deleterious variants adds further evidence to BRSK2 and other risk genes in Autism Spectrum Disorder.Research square · 2023Article
- A comprehensive Drosophila resource to identify key functional interactions between SARS-CoV-2 factors and host proteins.Cell reports · 2023Article
- SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia.Brain : a journal of neurology · 2023Article
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18 authors at 8 institutions in 4 countries.
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Abstract
TIAM Rac1-associated GEF 1 (TIAM1) regulates RAC1 signaling pathways that affect the control of neuronal morphogenesis and neurite outgrowth by modulating the actin cytoskeletal network. To date, TIAM1 has not been associated with a Mendelian disorder. Here, we describe five individuals with bi-allelic TIAM1 missense variants who have developmental delay, intellectual disability, speech delay, and seizures. Bioinformatic analyses demonstrate that these variants are rare and likely pathogenic. We found that the Drosophila ortholog of TIAM1, still life (sif), is expressed in larval and adult central nervous system (CNS) and is mainly expressed in a subset of neurons, but not in glia. Loss of sif reduces the survival rate, and the surviving adults exhibit climbing defects, are prone to severe seizures, and have a short lifespan. The TIAM1 reference (Ref) cDNA partially rescues the sif loss-of-function (LoF) phenotypes. We also assessed the function associated with three TIAM1 variants carried by two of the probands and compared them to the TIAM1 Ref cDNA function in vivo. TIAM1 p.Arg23Cys has reduced rescue ability when compared to TIAM1 Ref, suggesting that it is a partial LoF variant. In ectopic expression studies, both wild-type sif and TIAM1 Ref are toxic, whereas the three variants (p.Leu862Phe, p.Arg23Cys, and p.Gly328Val) show reduced toxicity, suggesting that they are partial LoF variants. In summary, we provide evidence that sif is important for appropriate neural function and that TIAM1 variants observed in the probands are disruptive, thus implicating loss of TIAM1 in neurological phenotypes in humans.
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