{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Dhindsa RS"],"funding":["NINDS NIH HHS"],"pagination":["e4"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4821085"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["1(1)"],"pubmed_abstract":["<h4>Objective</h4>To elucidate the functional consequences of epileptic encephalopathy-causing de novo mutations in DNM1 (A177P, K206N, G359A), which encodes a large mechanochemical GTPase essential for neuronal synaptic vesicle endocytosis.<h4>Methods</h4>HeLa and COS-7 cells transfected with wild-type and mutant DNM1 constructs were used for transferrin assays, high-content imaging, colocalization studies, Western blotting, and electron microscopy (EM). EM was also conducted on the brain sections of mice harboring a middle-domain Dnm1 mutation (Dnm1 (Ftfl)).<h4>Results</h4>We demonstrate that the expression of each mutant protein decreased endocytosis activity in a dominant-negative manner. One of the G-domain mutations, K206N, decreased protein levels. The G359A mutation, which occurs in the middle domain, disrupted higher-order DNM1 oligomerization. EM of mutant DNM1-transfected HeLa cells and of the Dnm1 (Ftfl) mouse brain revealed vesicle defects, indicating that the mutations likely interfere with DNM1's vesicle scission activity.<h4>Conclusion</h4>Together, these data suggest that the dysfunction of vesicle scission during synaptic vesicle endocytosis can lead to serious early-onset epilepsies."],"journal":["Neurology. Genetics"],"pubmed_title":["Epileptic encephalopathy-causing mutations in DNM1 impair synaptic vesicle endocytosis."],"pmcid":["PMC4821085"],"funding_grant_id":["U01 NS077303","R37 NS031348"],"pubmed_authors":["Johnson MR","Dhindsa RS","Goldstein DB","Heinzen EL","Krueger BJ","Petrovski S","Boumil RM","Bradrick SS","Frankel WN","Yao X","Petrou S"],"additional_accession":[]},"is_claimable":false,"name":"Epileptic encephalopathy-causing mutations in DNM1 impair synaptic vesicle endocytosis.","description":"<h4>Objective</h4>To elucidate the functional consequences of epileptic encephalopathy-causing de novo mutations in DNM1 (A177P, K206N, G359A), which encodes a large mechanochemical GTPase essential for neuronal synaptic vesicle endocytosis.<h4>Methods</h4>HeLa and COS-7 cells transfected with wild-type and mutant DNM1 constructs were used for transferrin assays, high-content imaging, colocalization studies, Western blotting, and electron microscopy (EM). EM was also conducted on the brain sections of mice harboring a middle-domain Dnm1 mutation (Dnm1 (Ftfl)).<h4>Results</h4>We demonstrate that the expression of each mutant protein decreased endocytosis activity in a dominant-negative manner. One of the G-domain mutations, K206N, decreased protein levels. The G359A mutation, which occurs in the middle domain, disrupted higher-order DNM1 oligomerization. EM of mutant DNM1-transfected HeLa cells and of the Dnm1 (Ftfl) mouse brain revealed vesicle defects, indicating that the mutations likely interfere with DNM1's vesicle scission activity.<h4>Conclusion</h4>Together, these data suggest that the dysfunction of vesicle scission during synaptic vesicle endocytosis can lead to serious early-onset epilepsies.","dates":{"release":"2015-01-01T00:00:00Z","publication":"2015 Jun","modification":"2026-05-29T20:40:17.056Z","creation":"2019-03-27T03:11:14Z"},"accession":"S-EPMC4821085","cross_references":{"pubmed":["27066543"],"doi":["10.1212/01.NXG.0000464295.65736.da"]}}