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The epileptic encephalopathies (EE) are a family of severe brain disorders manifesting early in life and characterized by spasms and/or intractable seizures. The relentless seizure activity impacts both cognitive and behavioral development in the patient . Many patients do not respond to typical anti-epileptic therapies and can experience early death. Of late, several novel mutations in newly revealed genes have been associated with the EEs. Through the efforts of such groups as the Epi4K and EuroEPINOMIC-RES consortiums, the Epilepsy Phenome/Genome Project and the Deciphering Developmental Disorders Study, de novo variants have surfaced in such genes as GABRB3, ALG13, GRIN1, NEDD4L, DNM1 and others . Whole-exome sequencing of patients has revealed 9 DNM1 variants . This research highlight describes our study of the mouse Dnm1 EE model to illustrate how certain classes of de novo variants may give rise to EEs and emphasize the contribution of specific neuronal populations to the comorbid phenotypes. Dynamin-1, the product of the DNM1 gene, is a large GTPase required for synaptic vesicle recycling in neurons . The highly brain specific Dynamin-1 is expressed during synaptogenesis through adulthood and undergoes alternative splicing resulting in the regulated expression of several splice variants. |
