Journal article

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

Abstract

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..

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Grants

Awarded by National Institute of Neurological Disorders and Stroke


Awarded by NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE


Funding Acknowledgements

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).