TBC1D20 deficiency causes Warburg Micro Syndrome in humans, characterized by multiple eye abnormalities, severe intellectual disability, and abnormal sexual development, but the molecular mechanisms remain unknown. Here, we identify TBC1D20 as a novel Rab11 GTPase-activating protein that coordinates vesicle transport and actin remodeling to regulate ciliogenesis. Depletion of TBC1D20 promotes Rab11 vesicle accumulation and actin deconstruction around the centrosome, facilitating the initiation of ciliogenesis even in cycling cells. Further investigations reveal enhanced Rab11-MICAL1 interaction upon TBC1D20 loss, activating the monooxygenase domain of MICAL1 and inducing F-actin depolymerization around the centrosome. This actin network reorganization facilitates vesicle trafficking and docking, ultimately promoting ciliogenesis. In summary, our work uncovers a coordinated ciliogenesis initiation mechanism via Rab11 activation. These findings underscore a pivotal role for TBC1D20 in early ciliogenesis, advancing our understanding of its spatiotemporal regulation and offering insights into the disease pathogenesis associated with TBC1D20 mutations.

The heterodimeric Rab3GAP complex is a guanine nucleotide exchange factor (GEF) for the Rab18 GTPase that regulates lipid droplet metabolism, ER-to-Golgi trafficking, secretion, and autophagy. Why both subunits of Rab3GAP are required for Rab18 GEF activity and the molecular basis of how Rab3GAP engages and activates its cognate substrate are unknown. Here we show that human Rab3GAP is conformationally flexible and potentially autoinhibited by the C-terminal domain of its Rab3GAP2 subunit. Our high-resolution structure of the catalytic core of Rab3GAP, determined by cryo-EM, shows that the Rab3GAP2 N-terminal domain binds Rab3GAP1 via an extensive interface. AlphaFold3 modelling analysis together with targeted mutagenesis and in vitro activity assay reveal that Rab3GAP likely engages its substrate Rab18 through an interface away from the switch and interswitch regions. Lastly, we find that three Warburg Micro Syndrome-associated missense mutations do not affect the overall architecture of Rab3GAP but instead likely interfere with substrate binding.

Warburg Micro syndrome (WARBM) is a rare autosomal recessive disorder characterized by ocular, neurodevelopmental, and neuroendocrine abnormalities, most commonly caused by RAB3GAP1 variants. RAB3GAP1 encodes the catalytic subunit of the RAB3 GTPase-activating protein (RAB3GAP), which regulates vesicular release and membrane trafficking through Rab GTPase modulation. Although in vitro studies suggest that RAB3GAP1 dysfunction impairs autophagy, the neuropathology of WARBM in the developing Human brain remains undocumented. Here, we present the first detailed neuropathological and molecular analysis of Human WARBM, based on two related cases: a 3-month-old infant and a 23-week gestation fetus with biallelic RAB3GAP1 pathogenic variants. Histological examination of the fetal cerebral cortex and cerebellum revealed selective vulnerability, with cortical plate thinning, while Purkinje cells appeared preserved. Consistently, immunohistochemistry demonstrated widespread RAB3GAP1 expression in the frontal cortex of controls, but no detectable staining in WARBM, coinciding with disrupted neurogenic niches, including reduced SOX2-positive progenitor cells, disorganized radial glia, and increased caspase-3 expression. These changes were associated with fewer DCX- and CTIP2-positive neurons, which may reflect a combination of altered neurogenesis, impaired neuronal migration and increased cell death. However, no gross brain malformations were observed in the fetus, whereas cortical malformations were evident in the 3-month-old infant, pointing to a progressive neurodevelopmental disruption potentially driven by fetal corticogenesis defects. These changes were accompanied by marked dysregulation of autophagy markers, linking impaired autophagy to disrupted cortical development. In contrast, autophagy disruption in the fetal lens was already associated with bilateral cataracts. Studies in patient-derived skin fibroblasts using immunocytochemistry, western blotting, and electron microscopy confirmed autophagy defects and tissue-specific consequences to RAB3GAP1 disruption in WARBM. Collectively, our findings provide the first in-depth neuropathological characterization of WARBM, highlighting the essential role of RAB3GAP1 in early Human and support autophagy as a key pathogenic feature in this severe disorder. The online version contains supplementary material available at 10.1186/s40478-025-02204-8.

Warburg micro syndrome is an extremely rare autosomal recessive genetic disorder with only 100 families documented worldwide. We present a safe and successful anesthetic management of a pediatric patient with Warburg micro syndrome utilizing total intravenous anesthesia (TIVA) and incisional Exparel.

The tumor microenvironment is a crucial factor in tumor occurrence and progression. The hypoxic microenvironment is widely present in tumor tissue and is a key endogenous factor accelerating tumor deterioration. The "blood stasis toxin" theory, as an emerging perspective in tumor research, is regarded as the unique "soil" in tumor progression from the perspective of traditional Chinese medicine(TCM) due to its dynamic evolution mechanism, which closely resembles the formation of the hypoxic microenvironment. Scientifically integrating TCM theories with the biological characteristics of tumors and exploring precise syndrome differentiation and treatment strategies are key to achieving comprehensive tumor prevention and control. This article focused on the hypoxic microenvironment of the tumor, elucidating its formation mechanisms and evolutionary processes and carefully analyzing the internal relationship between the "blood stasis toxin" theory and the hypoxic microenvironment. Additionally, it explored the interaction among blood stasis, toxic pathogens, and hypoxic environment and proposed micro-level prevention and treatment strategies targeting the hypoxic microenvironment based on the "blood stasis toxin" theory, aiming to provide TCM-based theoretical support and therapeutic approaches for precise regulation of the hypoxic microenvironment.