Febrile seizures, or febrile convulsions (FEB), represent the most common form of childhood seizures and are believed to be influenced by variations in several susceptibility genes. Most of the associated loci, however, remain 'orphan', i.e. the susceptibility genes they contain still remain to be identified. Further orphan loci have been mapped for a related disorder, genetic (generalized) epi...

The Rho family of GTPases are highly conserved molecular switches that control some of the most fundamental processes of cell biology, including morphogenesis, vesicular transport, cell division and motility. Guanine nucleotide-exchange factors (GEFs) are directly responsible for the activation of Rho-family GTPases in response to extracellular stimuli. In fission yeast, there are seven Dbl-rel...

Infection of cells with poliovirus induces a massive intracellular membrane reorganization to form vesicle-like structures where viral RNA replication occurs. The mechanism of membrane remodeling remains unknown, although some observations have implicated components of the cellular secretory and/or autophagy pathways. Recently, we showed that some members of the Arf family of small GTPases, whi...

Hundreds of mutations in the SCN1A sodium channel gene confer a wide spectrum of epileptic disorders, requiring efficient model systems to study cellular mechanisms and identify potential therapeutic targets. We recently demonstrated that Drosophila knock-in flies carrying the K1270T SCN1A mutation known to cause a form of genetic epilepsy with febrile seizures plus (GEFS+) exhibit a heat-induc...

21 Genetic epilepsy with febrile seizures plus (GEFS+) is an inherited epilepsy 22 which can result from mutations in at least four ion channel subunits. The majority of 23 the known GEFS+ mutations have been identified in SCN1A, the gene encoding 24 Nav1.1 α subunit. Protein kinases as critical modulators of sodium channels have been 25 closely related to the genesis of epilepsy. However, litt...

A key requirement for Rab function in membrane trafficking is site-specific activation by GDP-GTP exchange factors (GEFs), but the majority of the 63 human Rabs have no known GEF. We have performed a systematic characterization of the 17 human DENN domain proteins and demonstrated that they are specific GEFs for 10 Rabs. DENND1A/1B localize to clathrin patches at the plasma membrane and activat...

Ras and Rac are membrane-associated GTPases that function as molecular switches activating intracellular mitogen-activated protein kinase (MAPK) cascades and other effector pathways in response to extracellular signals [1]. Activation of Ras and Rac into their GTP-bound conformations is directly controlled by specific guanine-nucleotide exchange factors (GEFs), which catalyze GDP release. Sever...

Small Rho-GTPases are enzymes that are bound to GDP or GTP, which determines their inactive or active state, respectively. The exchange of GDP for GTP is catalyzed by so-called Rho-guanine nucleotide exchange factors (GEFs). Rho-GEFs are characterized by a Dbl-homology (DH) and adjacent Pleckstrin-homology (PH) domain that serves as enzymatic unit for the GDP/GTP exchange. Rho-GEFs show differe...