Dnm1

DNM1, or dynamin-1, is a member of the dynamin family of large GTPases encoded by the DNM1 gene in humans. It is predominantly expressed in neurons, where it participates in clathrin-mediated endocytosis and the scission of clathrin-coated vesicles during synaptic vesicle recycling. This process is essential for maintaining neurotransmitter release during repeated neural activity.

The dynamin-1 protein comprises an N-terminal GTPase domain that hydrolyzes GTP, followed by a middle domain, a pleckstrin homology (PH) domain that binds phosphoinositides, a GTPase effector domain, and a C-terminal proline-rich domain. It polymerizes into helical collars around the necks of budding vesicles and, through GTP hydrolysis, constricts and severes the vesicle from the plasma membrane. Its activity is regulated by interactions with SH3-domain containing partners such as amphiphysin, endophilin, and other dynamin adaptors.

Clinical significance: Pathogenic variants in DNM1 cause DNM1-related neurodevelopmental disorders, characterized by early-onset seizures and severe developmental delay. The condition often presents in infancy as epileptic encephalopathy, with hypotonia or general developmental impairment and seizures that can be refractory to treatment. Most reported cases arise from de novo heterozygous mutations. The disorder highlights the critical role of synaptic vesicle recycling in neural development and function.

Research notes: Model organisms with DNM1 dysfunction show impaired synaptic vesicle endocytosis and neurodevelopmental deficits; in mice, neuronal loss or severe synaptic dysfunction is observed, illustrating the essential function of dynamin-1 in the nervous system.