FGD6 expression in focal benign infantile epilepsy (FBIE): its potential role in epilepsy pathophysiology

PITOSSI FJ; GONZALEZ J; CASALIA M; KAUFFMAN M; CAVALIERE CANDEDO V; FARIAS MI; GARCIA CI; KOCHEN S; CASABONA JC; GALVAN DI

BUENOS AIRES

Congreso; Reunión Conjunta de Sociedades de Biociencias, LXII Reunión Cientifíca Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2017

Epilepsy is the third most common cause of neurological disorders.Focal Benign Infantile Epilepsy (FBIE) is the most prevalentin the paediatric population and belongs to the idiopathic epilepsygroup. A recent genetic analysis of familial FBIE determined FGD6as a potential candidate to be involved in epilepsy pathogenesis.The affected members presented a p.E276G mutation in homozygosis,suggesting mutated FGD6 as a probable cause of epilepsy inthis family. FGD6 function is not well established. It belongs to FGDfamily, in which some of the members have a known function suchas Cdc42 GEF (guanine exchange factors) activators. Cdc42 is aRho GTPase and has a key role in CNS, regulating cytoskeleton,synaptogenesis, spines and dendrite formation and axon guidance.We studied FGD6 expression in several culture models using, wildtype, FGD6 heterozygous and FGD6 homozygous cells. Our resultsshow that in a neuroepithelial culture model with induced pluripotentcells (IPS), FGD6 is expressed in neurons in the three experimentalgroups. In this model, FGD6 is found aggregated in the cytoplasmand plasma membrane when analysed cells from epileptic subjectswith a homozygous mutation in FGD6, compared to a homogeneousdistribution in wild type cells. Cytoskeleton studies in fibroblasts revealeda decrease in actin filaments, as well as disorganization ofthe cytoskeleton in epileptic patients. Finally, we studied by qRTPCRFGD6 expression in a SK-N-SH neuroblastoma cells, and weobserved a decrease in gene expression when the cells differentiateto a more mature phenotype (p≤0,05), followed by a raise in FGD6mRNA as the cells continue to differentiate. Our results suggest thatin neurons FGD6 expression is tightly regulated during cell maturation,and that FGD6 mutation affects cytoskeleton dynamics.