Epileptic encephalopathy-causing mutations in DNM1 impair synaptic vesicle endocytosis
Ryan S Dhindsa, Shelton S Bradrick, Xiaodi Yao, Erin L Heinzen, Slave Petrovski, Brian J Krueger, Michael R Johnson, Wayne N Frankel, Steven Petrou, Rebecca M Boumil, David B Goldstein
NEUROLOGY-GENETICS | LIPPINCOTT WILLIAMS & WILKINS | Published : 2015
OBJECTIVE: 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. METHODS: 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)). RESULTS: We demonstrate that the expression of each mutant protein decreased endocytosis activity in a dominant-negative manner. One of the G-doma..View full abstract
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Awarded by National Institute of Neurological Disorders and Stroke
Awarded by NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
This work was supported by grants from the National Institute of Neurological Disorders and Stroke (Epi4K-Administrative Core NS077274; Epi4K Sequencing, Biostatistics and Bioinformatics Core NS077303).