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

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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 (Dnm1Ftfl). Results: 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 Dnm1Ftfl mouse brain revealed vesicle defects, indicating that the mutations likely interfere with DNM1's vesicle scission activity. Conclusion: Together, these data suggest that the dysfunction of vesicle scission during synaptic vesicle endocytosis can lead to serious early-onset epilepsies.

Original languageEnglish (US)
Article numbere4
JournalNeurology: Genetics
Issue number1
StatePublished - Jun 2015
Externally publishedYes

ASJC Scopus subject areas

  • Clinical Neurology
  • Genetics(clinical)


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