RESUMEN
Heterozygous mutations in Myoclonin1/EFHC1 cause juvenile myoclonic epilepsy (JME), the most common form of genetic generalized epilepsies, while homozygous F229L mutation is associated with primary intractable epilepsy in infancy. Heterozygous mutations in adolescent JME patients produce subtle malformations of cortical and subcortical architecture, whereas homozygous F229L mutation in infancy induces severe brain pathology and death. However, the underlying pathological mechanisms for these observations remain unknown. We had previously demonstrated that EFHC1 is a microtubule-associated protein (MAP) involved in cell division and radial migration during cerebral corticogenesis. Here, we show that JME mutations, including F229L, do not alter the ability of EFHC1 to colocalize with the centrosome and the mitotic spindle, but act in a dominant-negative manner to impair mitotic spindle organization. We also found that mutants EFHC1 expression disrupted radial and tangential migration by affecting the morphology of radial glia and migrating neurons. These results show how Myoclonin1/EFHC1 mutations disrupt brain development and potentially produce structural brain abnormalities on which epileptogenesis is established.
Asunto(s)
Encéfalo/embriología , Encéfalo/metabolismo , Proteínas de Unión al Calcio/genética , Mutación , Epilepsia Mioclónica Juvenil/embriología , Epilepsia Mioclónica Juvenil/genética , Animales , Proteínas de Unión al Calcio/metabolismo , Ciclo Celular/genética , Línea Celular , Movimiento Celular/genética , Proliferación Celular , Humanos , Espacio Intracelular/metabolismo , Ratones , Neuroglía/metabolismo , Neuronas/metabolismo , Transporte de Proteínas , Ratas , Huso Acromático/genética , Huso Acromático/metabolismo , Células Madre/metabolismoRESUMEN
Juvenile Myoclonic Epilepsy (JME) accounts for almost 12% of all epilepsies and is one of the most frequent forms of genetic generalized epilepsies. Genetic studies have revealed that mutations in EFHC1 (EF-hand containing one) account for 3 to 9% of all cases around the world. This gene encodes a protein that is not an ion channel, and several studies have tried to find its cellular role. In this article, we review the various functions that have been proposed for this protein. Interestingly, all of them could affect brain development at different steps, suggesting that the developmental assembly of neural circuits may play a prominent role in JME.