The Warburg micro syndrome protein RAB3GAP1 modulates neuronal morphogenesis and interacts with axon elongation end ER-Golgi trafficking factors.

RAB3GAP1 is GTPase activating protein localized to the ER and Golgi compartments. In humans, mutations in RAB3GAP1 are the most common cause of Warburg Micro syndrome, a neurodevelopmental disorder associated with intellectual disability, microcephaly, and agenesis of the corpus callosum. We found that downregulation of RAB3GAP1 leads to a reduction in neurite outgrowth and complexity in human stem cell derived neurons. To further define the cellular function of RAB3GAP1, we sought to identify novel interacting proteins. We used a combination of mass spectrometry, co-immunoprecipitation and colocalization analysis and identified two novel interactors of RAB3GAP1: the axon elongation factor Dedicator of cytokinesis 7 (DOCK7) and the TATA modulatory factor 1 (TMF1) a modulator of Endoplasmic Reticulum (ER) to Golgi trafficking. To define the relationship between RAB3GAP1 and its two novel interactors, we analyzed their localization to different subcellular compartments in neuronal and non-neuronal cells with loss of RAB3GAP1. We find that RAB3GAP1 is important for the sub-cellular localization of TMF1 and DOCK7 across different compartments of the Golgi and endoplasmic reticulum. In addition, we find that loss of function mutations in RAB3GAP1 lead to dysregulation of pathways that are activated in response to the cellular stress like ATF6, MAPK, and PI3-AKT signaling. In summary, our findings suggest a novel role for RAB3GAP1 in neurite outgrowth that could encompass the regulation of proteins that control axon elongation, ER-Golgi trafficking, as well as pathways implicated in response to cellular stress.

Use of an Endoscopic Suturing Platform for the Management of Staple Line Dehiscence After Laparoscopic Sleeve Gastrectomy.

BACKGROUND: Management of staple line dehiscence following laparoscopic sleeve gastrectomy (LSG) varies based on local expertise and timing of presentation. We present our experience with an endoscopic suturing platform to treat patients with staple line dehiscence following LSG. METHODS: We included all patients who presented to our institution with a staple line dehiscence following LSG from 2005 through November 2017. All endoscopic suturing procedures were performed by a single interventional endoscopist. RESULTS: Five patients, ages 25-69 years, received treatment of staple line dehiscence at a median time of 22 days following LSG (range 13-335 days). Four out of the five patients received a stent at some point during their treatment. One patient with a chronic leak required gastrectomy and esophago-jejunostomy as a definitive treatment. The remaining four patients experienced resolution of the leak at a median of 48 days post-operatively (range 21-82 days). CONCLUSION: Endoscopic suturing may have a role in the management of leaks following LSG, as a primary treatment or as an adjunct to treatment with a stent. However, given that the technique requires considerable endoscopic expertise and in light of a number of other available therapeutic choices, further studies are required to better define the role of this technology in the algorithm of LSG-related leak management.