Functional analysis of EFR3A mutations associated with autism

Multiple nucleotide variants in the coding sequence of the EFR3A gene are associated with autism, but the protein’s function is not well understood. Pietro De Camilli and his colleagues at Yale University have used their expertise in neuronal signaling and cell biology to uncover the role of EFR3A in autism.

The list of autism susceptibility genes has grown dramatically in recent years, but the cellular and molecular dysfunction caused by autism-associated variants has been described through only a few examples. Through genome-wide studies of rare variants in autism spectrum disorders, Matthew State, who collaborates with De Camilli, tentatively linked EFR3A — a gene linked to lipid metabolism and highly expressed in brain — with autism¹.

De Camilli focused some of his research on the role of lipid metabolism, in particular lipids called phosphoinositides, in membrane and cytoskeleton dynamics at synapses, the junctions between neurons.

De Camilli and his colleagues have demonstrated, using biochemical and cell biological studies, that EFR3A plays a key role in regulating the subcellular localization and activity of an enzyme that generates phosphatidylinositol 4-phosphate, an important signaling lipid at the plasma membrane that has several functions in synaptic transmission²,³. They propose that dysfunction of EFR3A in autism may lead to alterations in phosphoinositide metabolism, and hence synaptic function, in the brain.