Abstract
The childhood epileptic encephalopathies (EE’s) are seizure disorders that broadly impact development including cognitive, sensory and motor progress with severe consequences and comorbidities. Recently, mutations in DNM1 (dynamin 1) have been implicated in two EE syndromes, Lennox-Gastaut Syndrome and Infantile Spasms. Dnm1 encodes dynamin 1, a large multimeric GTPase necessary for activity-dependent membrane recycling in neurons, including synaptic vesicle endocytosis. Dnm1Ftfl or “fitful” mice carry a spontaneous mutation in the mouse ortholog of DNM1 and recapitulate many of the disease features associated with human DNM1 patients, providing a relevant disease model of human EE’s. In order to examine the cellular etiology of seizures and behavioral and neurological comorbidities, we engineered a conditional Dnm1Ftfl mouse model of DNM1 EE. Observations of Dnm1 Ftfl/flox mice in combination with various neuronal subpopulation specific cre strains demonstrate unique seizure phenotypes and clear separation of major neurobehavioral comorbidities from severe seizures associated with the germline model. This demonstration of pleiotropy suggests that treating seizures per se may not prevent severe comorbidity observed in EE associated with dynamin-1 mutations, and is likely to have implications for other genetic forms of EE.
Highlights
Epileptic encephalopathies (EE’s) encompass a group of seizure disorders that impact overall development including cognitive, sensory and motor progress with severe developmental consequences and comorbidities
Dynamin 1 is a large multimeric protein that is critical for electro-chemical communication between neurons
Separation of Seizures from Comorbidities in Dnm1 "Fitful" Mutant Mice developmental outcomes in Dynamin 1 (DNM1) patients, we focus on “fitful” mice that carry a mutation in the dynamin 1 gene
Summary
Epileptic encephalopathies (EE’s) encompass a group of seizure disorders that impact overall development including cognitive, sensory and motor progress with severe developmental consequences and comorbidities. De novo missense mutations in DNM1 have been implicated in two EE’s, Lennox-Gastaut Syndrome and Infantile Spasms. At least eight patients have been documented with mutations in DNM1 [1,2,3]. This number is likely to grow based on the increasing efficacy of genetic diagnosis of EE by genome sequencing. All patients carry de novo heterozygous missense variants which are most likely dominant negative based on in vitro studies [4]. Studies of “fitful” mice, which carry a spontaneous missense mutation in the Dnm gene, have demonstrated a dominant negative effect of the mutant protein in vitro and the mice display seizures and neurosensory defects [5]
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